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1.
Eur Heart J ; 44(25): 2335-2345, 2023 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-37155355

RESUMO

AIMS: Apolipoprotein C-II (ApoC-II) is thought to activate lipoprotein lipase (LPL) and is therefore a possible target for treating hypertriglyceridemia. Its relationship with cardiovascular risk has not been investigated in large-scale epidemiologic studies, particularly allowing for apolipoprotein C-III (ApoC-III), an LPL antagonist. Furthermore, the exact mechanism of ApoC-II-mediated LPL activation is unclear. METHODS AND RESULTS: ApoC-II was measured in 3141 LURIC participants of which 590 died from cardiovascular diseases during a median (inter-quartile range) follow-up of 9.9 (8.7-10.7) years. Apolipoprotein C-II-mediated activation of the glycosylphosphatidylinositol high-density lipoprotein binding protein 1 (GPIHBP1)-LPL complex was studied using enzymatic activity assays with fluorometric lipase and very low-density lipoprotein (VLDL) substrates. The mean ApoC-II concentration was 4.5 (2.4) mg/dL. The relationship of ApoC-II quintiles with cardiovascular mortality exhibited a trend toward an inverse J-shape, with the highest risk in the first (lowest) quintile and lowest risk in the middle quintile. Compared with the first quintile, all other quintiles were associated with decreased cardiovascular mortality after multivariate adjustments including ApoC-III as a covariate (all P < 0.05). In experiments using fluorometric substrate-based lipase assays, there was a bell-shaped relationship for the effect of ApoC-II on GPIHBP1-LPL activity when exogenous ApoC-II was added. In ApoC-II-containing VLDL substrate-based lipase assays, GPIHBP1-LPL enzymatic activity was almost completely blocked by a neutralizing anti-ApoC-II antibody. CONCLUSION: The present epidemiologic data suggest that increasing low circulating ApoC-II levels may reduce cardiovascular risk. This conclusion is supported by the observation that optimal ApoC-II concentrations are required for maximal GPIHBP1-LPL enzymatic activity.


Assuntos
Doenças Cardiovasculares , Lipase Lipoproteica , Humanos , Apolipoproteína C-III , Lipase , Lipase Lipoproteica/metabolismo , Lipoproteínas VLDL/metabolismo , Triglicerídeos/metabolismo , Apolipoproteína C-II
2.
Stroke ; 54(4): 938-946, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36789775

RESUMO

BACKGROUND: Undetermined stroke etiology hampers optimal secondary prevention in a large proportion of young patients. We explored whether genetic screening for clonal hematopoiesis of indetermined potential (CHIP), a novel risk factor for stroke, could identify patients with myeloid precursor lesions or covert myeloid neoplasm requiring specific treatment. METHODS: We performed targeted sequencing on 56 genes recurrently mutated in hematologic neoplasms in a prospective cohort of patients with acute brain ischemia between 18 and 60 years. CHIP prevalence was compared with age-matched healthy controls from the Nijmegen Biomedical Study (n=1604) and the UK Biobank (n=101 678). Patients with suspicion of high-risk CHIP or myeloid neoplasm were invited for further hematologic evaluation. RESULTS: We included 248 consecutive patients (39% women) of whom 176 (71%) had cryptogenic stroke etiology. Fifty-one (21%) patients had CHIP, 3-fold more than in the general population (7.7% versus 2.6% for the Nijmegen Biomedical Study and 11.9% versus 4.1% for UK Biobank; P<0.001 for both). Patients with CHIP were older (median [interquartile range], 53 [50-59] versus 51 [41-56] years; P<0.001), had higher carotid intima-media thickness (0.68 [0.58-0.80] versus 0.59 [0.51-0.73] mm; P=0.009), and had higher burden of atherosclerosis (29.4% versus 16.7%; P=0.04). We invited 11 patients (4.4%) for further hematologic assessment, which in 7 led to the diagnosis of high-risk CHIP and in 2 to the new diagnosis of a myeloproliferative neoplasm with indication for cytoreductive therapy. CONCLUSIONS: Using genetic screening for myeloid disorders in patients with stroke of predominantly undetermined etiology, we found a 3-fold higher CHIP prevalence than in the general population. We identified high-risk CHIP and previously covert myeloproliferative neoplasms as potential stroke etiologies in 4.4% and 1% of patients, respectively. Our findings demonstrate the diagnostic and therapeutic yield of genetic screening in young patients with stroke. Future studies should investigate the role of CHIP for stroke recurrence and optimal secondary prevention.


Assuntos
Neoplasias Hematológicas , Acidente Vascular Cerebral , Humanos , Feminino , Masculino , Hematopoiese Clonal , Prevalência , Estudos Prospectivos , Espessura Intima-Media Carotídea , Hematopoese/genética , Mutação , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/genética
3.
J Lipid Atheroscler ; 11(2): 161-177, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35656151

RESUMO

Objective: Impaired cardiac efficiency is a hallmark of diabetic cardiomyopathy in models of type 2 diabetes. Adiponectin receptor 1 (AdipoR1) deficiency impairs cardiac efficiency in non-diabetic mice, suggesting that hypoadiponectinemia in type 2 diabetes may contribute to impaired cardiac efficiency due to compromised AdipoR1 signaling. Thus, we investigated whether targeting cardiac adiponectin receptors may improve cardiac function and energetics, and attenuate diabetic cardiomyopathy in type 2 diabetic mice. Methods: A non-selective adiponectin receptor agonist, AdipoRon, and vehicle were injected intraperitoneally into Eight-week-old db/db or C57BLKS/J mice for 10 days. Cardiac morphology and function were evaluated by echocardiography and working heart perfusions. Results: Based on echocardiography, AdipoRon treatment did not alter ejection fraction, left ventricular diameters or left ventricular wall thickness in db/db mice compared to vehicle-treated mice. In isolated working hearts, an impairment in cardiac output and efficiency in db/db mice was not improved by AdipoRon. Mitochondrial respiratory capacity, respiration in the presence of oligomycin, and 4-hydroxynonenal levels were similar among all groups. However, AdipoRon induced a marked shift in the substrate oxidation pattern in db/db mice towards increased reliance on glucose utilization. In parallel, the diabetes-associated increase in serum triglyceride levels in vehicle-treated db/db mice was blunted by AdipoRon treatment, while an increase in myocardial triglycerides in vehicle-treated db/db mice was not altered by AdipoRon treatment. Conclusion: AdipoRon treatment shifts myocardial substrate preference towards increased glucose utilization, likely by decreasing fatty acid delivery to the heart, but was not sufficient to improve cardiac output and efficiency in db/db mice.

5.
Indian J Pediatr ; 88(2): 147-153, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32472350

RESUMO

OBJECTIVES: To analyse the clinical and molecular spectrum of Lipoprotein Lipase (LPL) deficiency and to highlight the effect of a cost-effective indigenous diet for management of this disorder. METHODS: This is a single-centre retrospective study. Fifteen patients from 14 kindreds with severe hypertriglyceridemia (more than 1000 mg/dl) were evaluated for a period of 12.5 y at Amrita Institute of Medical Sciences, Kerala, India. RESULTS: Thirteen of 15 patients were referred after incidental detection of lipemic plasma, 1/15 had chylothorax in the neonatal period and 1/15 had pancreatitis. The mean age of presentation was 7 mo (ranging from 2 d to 4 y), and 20% of the patients had a positive history of consanguinity. Hepatomegaly (15/15), splenomegaly (9/15) and lipemia retinalis (14/15) were common findings. Lipemia retinalis was a useful non-invasive diagnostic tool. All the patients were subjected to diet modification and followed up at regular intervals. Fourteen of 15 complied with the diet, resulting in a dramatic improvement in the fasting lipid profile; only 1/15 developed pancreatitis. Genetic screening analysis was offered to 14/15 patients (1/15 was lost to follow-up); six different variants were identified, of which two were novel variants. CONCLUSIONS: Lipemic serum, chylothorax and recurrent pancreatitis in children should raise the suspicion of Lipoprotein Lipase deficiency. Early diagnosis and prompt initiation of a stringent fat-restricted diet are the keys to success for the management of LPL deficiency and prevention of pancreatitis.


Assuntos
Hiperlipoproteinemia Tipo I , Hipertrigliceridemia , Criança , Humanos , Hiperlipoproteinemia Tipo I/diagnóstico , Hiperlipoproteinemia Tipo I/genética , Índia/epidemiologia , Recém-Nascido , Lipase Lipoproteica/genética , Estudos Retrospectivos
6.
Atherosclerosis ; 311: 84-90, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32949947

RESUMO

BACKGROUND AND AIMS: Very rare loss-of-function mutations in the apolipoprotein C3 (APOC3) gene have been associated with low circulating apoC-III, low triglycerides, and reduced cardiovascular risk. We aimed to analyze the impact of common APOC3 variants on key parameters of lipid metabolism and coronary artery disease in the largest sample so far. METHODS: Common variants in APOC3 were tested for associations with circulating apoC-III, lipids, and apolipoprotein B (apoB) in 3041 participants of the LUdwigshafen RIsk and Cardiovascular health study (LURIC). These variants were then tested for associations with coronary artery disease in a meta-analysis comprising up to 332,389 participants of the CARDIOGRAMplusC4D consortium and the UK Biobank. RESULTS: The mean (standard deviation) apoC-III concentration was 14.6 (5.1) mg/dl. Seven common variants in APOC3 (rs734104, rs4520, rs5142, rs5141, rs5130, rs5128, and rs4225) were associated with circulating apoC-III (all p < 0.05). The alleles that modestly raised apoC-III were also associated with markedly higher total triglycerides and very low density lipoprotein (VLDL) triglycerides and cholesterol (all p < 0.05), but not with low density lipoprotein (LDL) cholesterol and total apoB (all p > 0.05). These variants were not associated with coronary artery disease in the CARDIOGRAMplusC4D consortium and the UK Biobank (all p > 0.1). CONCLUSIONS: Modest, genetically caused elevations of apoC-III are associated with a marked increase of triglyceride-rich lipoproteins but not with an increase of LDL cholesterol, total apoB, and coronary artery disease. Whether effective inhibition of apoC-III production with antisense oligomers will be instrumental to reduce cardiovascular risk remains to be demonstrated.


Assuntos
Doença da Artéria Coronariana , Hipertrigliceridemia , Apolipoproteína C-III/genética , Apolipoproteínas B/genética , VLDL-Colesterol , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/genética , Humanos , Lipoproteínas VLDL , Triglicerídeos
7.
Eur J Nutr ; 59(4): 1399-1411, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31129702

RESUMO

PURPOSE: Short telomeres and B vitamin deficiencies have been proposed as risk factors for age-related diseases and mortality that interact through oxidative stress and inflammation. However, available data to support this concept are insufficient. We aimed to investigate the predictive role of B vitamins and homocysteine (HCY) for mortality in cardiovascular patients. We explored potential relationships between HCY, B vitamins, relative telomere length (RTL), and indices of inflammation. METHODS: Vitamin B6, HCY, interleukin-6 (IL-6), high-sensitive-C-reactive protein (hs-CRP), and RTL were measured in participants of the Ludwigshafen Risk and Cardiovascular Health Study. Death events were recorded over a median follow-up of 9.9 years. RESULTS: All-cause mortality increased with higher concentrations of HCY and lower vitamin B6. Patients in the 4th quartile of HCY and vitamin B6 had hazard ratios (HR) for all-cause mortality of 2.77 (95% CI 2.28-3.37) and 0.41(95% CI 0.33-0.49), respectively, and for cardiovascular mortality of 2.78 (95% CI 2.29-3.39) and 0.40 (95% CI 0.33-0.49), respectively, compared to those in the 1st quartile. Multiple adjustments for confounders did not change these results. HCY and vitamin B6 correlated with age-corrected RTL (r = - 0.086, p < 0.001; r = 0.04, p = 0.031, respectively), IL-6 (r = 0.148, p < 0.001; r = - 0.249, p < 0.001, respectively), and hs-CRP (r = 0.101, p < 0.001; r = - 0.320, p < 0.001, respectively). Subjects with the longest telomeres had a significantly higher concentration of vitamin B6, but lower concentrations of HCY, IL-6, and hs-CRP. Multiple regression analyses identified HCY as an independent negative predictor of age-corrected RTL. CONCLUSIONS: In conclusion, hyperhomocysteinemia and vitamin B6 deficiency are risk factors for death from any cause. Hyperhomocysteinemia and vitamin B6 deficiency correlate with increased mortality. This correlation might, at least partially, be explained by accelerated telomere shortening induced by oxidative stress and systemic inflammation in these circumstances.


Assuntos
Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/mortalidade , Homocisteína/sangue , Inflamação/epidemiologia , Encurtamento do Telômero , Vitamina B 6/sangue , Feminino , Alemanha/epidemiologia , Inquéritos Epidemiológicos/métodos , Inquéritos Epidemiológicos/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco
8.
J Mol Cell Cardiol ; 133: 138-147, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31201798

RESUMO

BACKGROUND: Sepsis-induced cardiomyopathy contributes to the high mortality of septic shock in critically ill patients. Since the underlying mechanisms are incompletely understood, we hypothesized that sepsis-induced impairment of sirtuin 3 (SIRT3) activity contributes to the development of septic cardiomyopathy. METHODS AND RESULTS: Treatment of mice with lipopolysaccharide (LPS) for 6 h resulted in myocardial NAD+ depletion and increased mitochondrial protein acetylation, indicating impaired myocardial SIRT3 activity due to NAD+ depletion. LPS treatment also resulted in impaired cardiac output in isolated working hearts, indicating endotoxemia-induced cardiomyopathy. Maintaining normal myocardial NAD+ levels in LPS-treated mice by Poly(ADP-ribose)polymerase 1 (PARP1) deletion prevented cardiac dysfunction, whereas additional SIRT3 deficiency blunted this beneficial effect, indicating that impaired SIRT3 activity contributes to cardiac dysfunction in endotoxemia. Measurements of mitochondrial ATP synthesis suggest that LPS-induced contractile dysfunction may result from cardiac energy depletion due to impaired SIRT3 activity. Pharmacological inhibition of mitochondrial calpains using MDL28170 normalized LPS-induced cleavage of the ATP5A1 subunit of ATP synthase and normalized contractile dysfunction, suggesting that cardiac energy depletion may result from calpain-mediated cleavage of ATP5A1. These beneficial effects were completely blunted by SIRT3 deficiency. Finally, a gene set enrichment analysis of hearts of patients with septic, ischemic or dilated cardiomyopathy revealed a sepsis-specific suppression of SIRT3 deacetylation targets, including ATP5A1, indicating a functional relevance of SIRT3-dependent pathways in human sepsis. CONCLUSIONS: Impaired SIRT3 activity may mediate cardiac dysfunction in endotoxemia by facilitating calpain-mediated disruption of ATP synthesis, suggesting SIRT3 activation as a potential therapeutic strategy to treat septic cardiomyopathy.


Assuntos
Trifosfato de Adenosina/biossíntese , Calpaína/metabolismo , Endotoxemia/complicações , Cardiopatias/etiologia , Cardiopatias/metabolismo , Sirtuína 3/metabolismo , Animais , Calpaína/antagonistas & inibidores , Citocinas , Modelos Animais de Doenças , Endotoxemia/etiologia , Ativação Enzimática , Cardiopatias/fisiopatologia , Humanos , Masculino , Camundongos , Camundongos Knockout , Mitocôndrias Cardíacas/metabolismo , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , Sepse/complicações , Sepse/etiologia , Transdução de Sinais , Sirtuína 3/genética
9.
BMC Syst Biol ; 13(1): 12, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30670016

RESUMO

BACKGROUND: Cholesterylester transfer protein (CETP) modulates the composition of various lipoproteins associated with cardiovascular disease. Despite its central role in lipoprotein metabolism, its mode of action is still not fully understood. Here we present a simple way to estimate CETP-mediated lipid fluxes between different lipoprotein fractions. RESULTS: The model derived adequately describes the observed findings, especially regarding low- and high dense lipoproteins (LDL and HDL), delivering correlation coefficients of R2 = 0.567 (p < 0.001) and R2 = 0.466 (p < 0.001), respectively. These estimated fluxes correlate best among all other measured concentrations and 'lipid per lipoprotein' ratios to the observed fluxes. CONCLUSION: Our model approach is independent of CETP-action's exact mechanistic mode. It is simple and easy to apply, and may be a useful tool in revealing CETP's ambiguous role in lipid metabolism. The model mirrors a diffusion-like exchange of triglycerides between lipoproteins. Cholesteryl ester and triglyceride concentrations measured in HDL, LDL and VLDL are sufficient to apply the model on a plasma sample.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Modelos Biológicos , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Transporte Biológico , Humanos
10.
Artigo em Inglês | MEDLINE | ID: mdl-31920982

RESUMO

Decreased serum adiponectin levels in type 2 diabetes has been linked to the onset of mitochondrial dysfunction in diabetic complications by impairing AMPK-SIRT1-PGC-1α signaling via impaired adiponectin receptor 1 (AdipoR1) signaling. Here, we aimed to characterize the previously undefined role of disrupted AdipoR1 signaling on the mitochondrial protein composition of cardiac, renal, and hepatic tissues as three organs principally associated with diabetic complications. Comparative proteomics were performed in mitochondria isolated from the heart, kidneys and liver of Adipor1 -/- mice. A total of 790, 1,573, and 1,833 proteins were identified in cardiac, renal and hepatic mitochondria, respectively. While 121, 98, and 78 proteins were differentially regulated in cardiac, renal, and hepatic tissue of Adipor1-/- mice, respectively; only 15 proteins were regulated in the same direction across all investigated tissues. Enrichment analysis of differentially expressed proteins revealed disproportionate representation of proteins involved in oxidative phosphorylation conserved across tissue types. Curated pathway analysis identified HNF4, NRF1, LONP, RICTOR, SURF1, insulin receptor, and PGC-1α as candidate upstream regulators. In high fat-fed non-transgenic mice with obesity and insulin resistance, AdipoR1 gene expression was markedly reduced in heart (-70%), kidney (-80%), and liver (-90%) (all P < 0.05) as compared to low fat-fed mice. NRF1 was the only upstream regulator downregulated both in Adipor1-/- mice and in high fat-fed mice, suggesting common mechanisms of regulation. Thus, AdipoR1 signaling regulates mitochondrial protein composition across all investigated tissues in a functionally conserved, yet molecularly distinct, manner. The biological significance and potential implications of impaired AdipoR1 signaling are discussed.

11.
Curr Drug Deliv ; 15(9): 1261-1270, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29779479

RESUMO

BACKGROUND: Nanoscale drug delivery systems accumulate in solid tumors preferentially by the enhanced permeation and retention effect (EPR-effect). Nevertheless, only a miniscule fraction of a given dosage reaches the tumor, while >90% of the given drug ends up in otherwise healthy tissues, leading to the severe toxic reactions observed during chemotherapy. Once accumulation in the tumor has reached its maximum, extracorporeal elimination of circulating nanoparticles by plasmapheresis can diminish toxicities. OBJECTIVE: In this study, we investigated the effect of dosing and plasmapheresis timing on adverse events and antitumor efficacy in a syngeneic rat tumor model. METHODS: MAT-B-III cells transfected with a luciferase reporter plasmid were inoculated into female Fisher rats, and pegylated liposomal doxorubicin (PLD) was used for treatment. Plasmapheresis was performed in a discontinuous manner via centrifugation and subsequent filtration of isolated plasma. RESULTS: Bioluminescence measurements of tumor growth could not substitute caliper measurements of tumor size. In the control group, raising the dosage above 9 mg PLD/kg body weight did not increase therapeutic efficacy in our fully immunocompetent animal model. Plasmapheresis was best done 36 h after injecting PLD, leading to similar antitumor efficacy with significantly less toxicity. Plasmapheresis 24 h after injection interfered with therapeutic efficacy, while plasmapheresis after 48 h led to fewer side effects but also to increased weight loss. CONCLUSION: Long-circulating nanoparticles offer the unique possibility to eliminate the excess of circulating particles after successful accumulation in tumors by EPR, thereby reducing toxicities and likely toxicity-related therapeutic limitations.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/análogos & derivados , Plasmaferese , Animais , Antibióticos Antineoplásicos/efeitos adversos , Antibióticos Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Doxorrubicina/efeitos adversos , Doxorrubicina/química , Doxorrubicina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Lipossomos/química , Medições Luminescentes , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Tamanho da Partícula , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Ratos , Ratos Endogâmicos F344 , Propriedades de Superfície , Células Tumorais Cultivadas
12.
Curr Cardiol Rep ; 20(7): 56, 2018 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-29802474

RESUMO

PURPOSE OF REVIEW: Today, statins are the first choice to lower LDL cholesterol and concomitantly the risk of atherosclerotic cardiovascular disease. There is a significant minority of statin-treated patients who are more susceptible to occasionally serious side effects that may increase morbidity and lead to compliance problems or the discontinuation of therapy. This review addresses the question of whether genetics can provide meaningful insights into the risk of statin side effects or therapy success. RECENT FINDINGS: The use of genome-wide association studies has significantly reduced the number of predictive genetic markers for statin effects, and the isolated effect of the surviving markers is low; more promising are approaches to stratify patients with genetic risk scores. Patients reveal a pronounced individual response to the administration of statins. The idea of being able to adequately describe this variability with single genetic markers has failed, genetic risk scores will be the method of choice.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Dislipidemias/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Medicina de Precisão/métodos , Doenças Cardiovasculares/genética , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/genética , Dislipidemias/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Doenças Musculares/induzido quimicamente , Doenças Musculares/genética , Testes Farmacogenômicos/métodos
13.
Basic Res Cardiol ; 113(1): 8, 2018 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-29288409

RESUMO

Genetic factors are known to modulate cardiac susceptibility to ventricular hypertrophy and failure. To determine how strain influences the transcriptional response to pressure overload-induced heart failure (HF) and which of these changes accurately reflect the human disease, we analyzed the myocardial transcriptional profile of mouse strains with high (C57BL/6J) and low (129S1/SvImJ) susceptibility for HF development, which we compared to that of human failing hearts. Following transverse aortic constriction (TAC), C57BL/6J mice developed overt HF while 129S1/SvImJ did not. Despite a milder aortic constriction, impairment of ejection fraction and ventricular remodeling (dilation, fibrosis) was more pronounced in C57BL/6J mice. Similarly, changes in myocardial gene expression were more robust in C57BL/6J (461 genes) compared to 129S1/SvImJ mice (71 genes). When comparing these patterns to human dilated cardiomyopathy (1344 genes), C57BL/6J mice tightly grouped to human hearts. Overlay and bioinformatic analysis of the transcriptional profiles of C57BL/6J mice and human failing hearts identified six co-regulated genes (POSTN, CTGF, FN1, LOX, NOX4, TGFB2) with established link to HF development. Pathway enrichment analysis identified angiotensin and IGF-1 signaling as most enriched putative upstream regulator and pathway, respectively, shared between TAC-induced HF in C57BL/6J mice and in human failing hearts. TAC-induced heart failure in C57BL/6J mice more closely reflects the gene expression pattern of human dilated cardiomyopathy compared to 129S1/SvImJ mice. Unbiased as well as targeted gene expression and pathway analyses identified periostin, angiotensin signaling, and IGF-1 signaling as potential causes of increased HF susceptibility in C57BL/6J mice and as potentially useful drug targets for HF treatment.


Assuntos
Cardiomiopatia Dilatada/genética , Regulação da Expressão Gênica , Insuficiência Cardíaca/genética , Hipertrofia Ventricular Esquerda/genética , Função Ventricular Esquerda/genética , Animais , Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/fisiopatologia , Estudos de Casos e Controles , Modelos Animais de Doenças , Progressão da Doença , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Predisposição Genética para Doença , Insuficiência Cardíaca/fisiopatologia , Hipertrofia Ventricular Esquerda/complicações , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Fenótipo , Especificidade da Espécie , Transcriptoma , Remodelação Ventricular/genética
14.
J Lipid Res ; 57(5): 882-93, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27015744

RESUMO

Lipoproteins play a key role in the development of CVD, but the dynamics of lipoprotein metabolism are difficult to address experimentally. This article describes a novel two-step combined in vitro and in silico approach that enables the estimation of key reactions in lipoprotein metabolism using just one blood sample. Lipoproteins were isolated by ultracentrifugation from fasting plasma stored at 4°C. Plasma incubated at 37°C is no longer in a steady state, and changes in composition may be determined. From these changes, we estimated rates for reactions like LCAT (56.3 µM/h), ß-LCAT (15.62 µM/h), and cholesteryl ester (CE) transfer protein-mediated flux of CE from HDL to IDL/VLDL (21.5 µM/h) based on data from 15 healthy individuals. In a second step, we estimated LDL's HL activity (3.19 pools/day) and, for the very first time, selective CE efflux from LDL (8.39 µM/h) by relying on the previously derived reaction rates. The estimated metabolic rates were then confirmed in an independent group (n = 10). Although measurement uncertainties do not permit us to estimate parameters in individuals, the novel approach we describe here offers the unique possibility to investigate lipoprotein dynamics in various diseases like atherosclerosis or diabetes.


Assuntos
Lipoproteínas LDL/sangue , Adulto , Algoritmos , Proteínas de Transferência de Ésteres de Colesterol/fisiologia , Simulação por Computador , Esterificação , Feminino , Humanos , Hidrólise , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Fosfatidilcolina-Esterol O-Aciltransferase/fisiologia , Triglicerídeos/fisiologia , Adulto Jovem
15.
Can J Physiol Pharmacol ; 94(1): 72-80, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26524632

RESUMO

Lack of the mitochondrial deacetylase sirtuin 3 (SIRT3) impairs mitochondrial function and increases the susceptibility to induction of the mitochondrial permeability transition pore. Because these alterations contribute to myocardial ischemia-reperfusion (IR) injury, we hypothesized that SIRT3 deficiency may increase cardiac injury following myocardial IR. Hearts of 10-week-old mice were perfused in the isolated working mode and subjected to 17.5 min of global no-flow ischemia, followed by 30 min of reperfusion. Measurements before ischemia revealed a decrease in cardiac power (-20%) and rate pressure product (-15%) in SIRT3(-/-) mice. Mitochondrial state 3 respiration (-15%), ATP synthesis (-39%), and ATP/O ratios (-29%) were decreased in hearts of SIRT3(-/-) mice. However, percent recovery of cardiac power (WT 94% ± 9%; SIRT3(-/-) 89% ± 9%) and rate pressure product (WT 89% ± 16%; SIRT3(-/-) 96% ± 3%) following IR was similar in both groups. Myocardial infarct size was not increased in SIRT3(-/-) mice following permanent ligation of the left anterior descending coronary artery (LAD). Left ventricular pressure and dP/dtmax, and mitochondrial respiration and ATP synthesis were not different between groups following LAD ligation. Thus, despite pre-existing defects in cardiac function and mitochondrial respiratory capacity in SIRT3(-/-) mice, SIRT3 deficiency does not additionally impair cardiac function following IR or following myocardial infarction.


Assuntos
Traumatismo por Reperfusão Miocárdica/fisiopatologia , Sirtuína 3/deficiência , Trifosfato de Adenosina/biossíntese , Animais , Metabolismo Energético , Técnicas In Vitro , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Knockout , Mitocôndrias Cardíacas/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Poro de Transição de Permeabilidade Mitocondrial , Contração Miocárdica , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/genética , Consumo de Oxigênio , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 3/genética , Sirtuína 3/fisiologia
16.
Basic Res Cardiol ; 110(4): 36, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25962702

RESUMO

Sirtuin 3 (SIRT3) is a mitochondrial NAD(+)-dependent deacetylase that regulates energy metabolic enzymes by reversible protein lysine acetylation in various extracardiac tissues. The role of SIRT3 in myocardial energetics and in the development of mitochondrial dysfunction in cardiac pathologies, such as the failing heart, remains to be elucidated. To investigate the role of SIRT3 in the regulation of myocardial energetics and function SIRT3(-/-) mice developed progressive age-related deterioration of cardiac function, as evidenced by a decrease in ejection fraction and an increase in enddiastolic volume at 24 but not 8 weeks of age using echocardiography. Four weeks following transverse aortic constriction, ejection fraction was further decreased in SIRT3(-/-) mice compared to WT mice, accompanied by a greater degree of cardiac hypertrophy and fibrosis. In isolated working hearts, a decrease in cardiac function in SIRT3(-/-) mice was accompanied by a decrease in palmitate oxidation, glucose oxidation, and oxygen consumption, whereas rates of glycolysis were increased. Respiratory capacity and ATP synthesis were decreased in cardiac mitochondria of SIRT3(-/-) mice. HPLC measurements revealed a decrease of the myocardial ATP/AMP ratio and of myocardial energy charge. Using LC-MS/MS, we identified increased acetylation of 84 mitochondrial proteins, including 6 enzymes of fatty acid import and oxidation, 50 subunits of the electron transport chain, and 3 enzymes of the tricarboxylic acid cycle. Lack of SIRT3 impairs mitochondrial and contractile function in the heart, likely due to increased acetylation of various energy metabolic proteins and subsequent myocardial energy depletion.


Assuntos
Mitocôndrias Cardíacas/fisiologia , Contração Miocárdica , Sirtuína 3/fisiologia , Animais , Ciclo do Ácido Cítrico , Metabolismo Energético , Masculino , Camundongos , Camundongos Knockout , Fosforilação Oxidativa
17.
Basic Res Cardiol ; 110(4): 37, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25982881

RESUMO

Hypoadiponectinemia is an independent predictor of cardiovascular disease, impairs mitochondrial function in skeletal muscle, and has been linked to the pathogenesis of Type 2 diabetes. In models of Type 2 diabetes, myocardial mitochondrial function is impaired, which is improved by increasing serum adiponectin levels. We aimed to define the roles of adiponectin receptor 1 (AdipoR1) and 2 (AdipoR2) in adiponectin-evoked regulation of mitochondrial function in the heart. In isolated working hearts in mice lacking AdipoR1, myocardial oxygen consumption was increased without a concomitant increase in cardiac work, resulting in reduced cardiac efficiency. Activities of mitochondrial oxidative phosphorylation (OXPHOS) complexes were reduced, accompanied by reduced OXPHOS protein levels, phosphorylation of AMP-activated protein kinase, sirtuin 1 activity, and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) signaling. Decreased ATP/O ratios suggested myocardial mitochondrial uncoupling in AdipoR1-deficient mice, which was normalized by lowering increased mitochondrial 4-hydroxynonenal levels following treatment with the mitochondria-targeted antioxidant Mn (III) tetrakis (4-benzoic acid) porphyrin. Lack of AdipoR2 did not impair mitochondrial function and coupling in the heart. Thus, lack of AdipoR1 impairs myocardial mitochondrial function and coupling, suggesting that impaired AdipoR1 signaling may contribute to mitochondrial dysfunction and mitochondrial uncoupling in Type 2 diabetic hearts.


Assuntos
Mitocôndrias Cardíacas/fisiologia , Receptores de Adiponectina/fisiologia , Proteínas Quinases Ativadas por AMP/fisiologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Contração Miocárdica , Fosforilação Oxidativa , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/fisiologia , Fatores de Transcrição/fisiologia
18.
PLoS One ; 10(3): e0119416, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25785965

RESUMO

Adiponectin deficiency leads to increased myocardial infarct size following ischemia reperfusion and to exaggerated cardiac hypertrophy following pressure overload, entities that are causally linked to mitochondrial dysfunction. In skeletal muscle, lack of adiponectin results in impaired mitochondrial function. Thus, it was our objective to investigate whether adiponectin deficiency impairs mitochondrial energetics in the heart. At 8 weeks of age, heart weight-to-body weight ratios were not different between adiponectin knockout (ADQ-/-) mice and wildtypes (WT). In isolated working hearts, cardiac output, aortic developed pressure and cardiac power were preserved in ADQ-/- mice. Rates of fatty acid oxidation, glucose oxidation and glycolysis were unchanged between groups. While myocardial oxygen consumption was slightly reduced (-24%) in ADQ-/- mice in isolated working hearts, rates of maximal ADP-stimulated mitochondrial oxygen consumption and ATP synthesis in saponin-permeabilized cardiac fibers were preserved in ADQ-/- mice with glutamate, pyruvate or palmitoyl-carnitine as a substrate. In addition, enzymatic activity of respiratory complexes I and II was unchanged between groups. Phosphorylation of AMP-activated protein kinase and SIRT1 activity were not decreased, expression and acetylation of PGC-1α were unchanged, and mitochondrial content of OXPHOS subunits was not decreased in ADQ-/- mice. Finally, increasing energy demands due to prolonged subcutaneous infusion of isoproterenol did not differentially affect cardiac contractility or mitochondrial function in ADQ-/- mice compared to WT. Thus, mitochondrial and contractile function are preserved in hearts of mice lacking adiponectin, suggesting that adiponectin may be expendable in the regulation of mitochondrial energetics and contractile function in the heart under non-pathological conditions.


Assuntos
Adiponectina/deficiência , Metabolismo Energético , Erros Inatos do Metabolismo/metabolismo , Mitocôndrias Cardíacas/metabolismo , Contração Miocárdica/fisiologia , Miocárdio/metabolismo , Adiponectina/genética , Adiponectina/metabolismo , Adiponectina/fisiologia , Animais , Coração/fisiologia , Masculino , Camundongos , Camundongos Knockout
19.
Cardiovasc Diabetol ; 13: 155, 2014 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-25408147

RESUMO

BACKGROUND: Secreted frizzled-related proteins (SFRP) are regulators of Wnt-signalling. SFRP4 has been shown to regulate insulin exocytosis and is overexpressed in type 2 diabetes mellitus. Here we characterized the relation of SFRP4 to glucose and triglyceride metabolism and outcomes in patients with stable coronary artery disease on statin treatment in the prospective Homburg Cream & Sugar Study (NCT00628524). METHODS: Fasting SFRP4 concentrations were measured by ELISA in 504 consecutive patients with stable CAD confirmed by angiography. RESULTS: The median age was 68 years and 83% of patients were male. Oral glucose tolerance tests were performed in all patients without known diabetes for metabolic characterization. 24.4% of patients showed normal glucose tolerance, 29.4% impaired glucose tolerance and 46.2% diabetes mellitus. SFRP4 concentrations correlated with insulin (R = 0.153, p = 0.001), HbA1c (R = 0.166, p < 0.0001), fasting triglycerides (R = 0.113, p = 0.011) and higher triglycerides after lipid challenge (postprandial triglycerides R = 0.124, p = 0.005; AUC R = 0.134, p = 0.003). Higher SFRP4 concentrations were associated with type 2 diabetes, metabolic syndrome, and severity of diabetes. The primary outcome was the composite of cardiovascular death and cardiovascular hospitalization within 48 months follow-up. Comparison of event-free survival between SFRP4 tertiles showed that SFRP4 concentrations were not predictive for cardiovascular outcome. CONCLUSIONS: SFRP4 concentrations are associated with impaired glucose and triglyceride metabolism but do not predict cardiovascular outcome in patients with stable coronary artery disease on treatment.


Assuntos
Doença da Artéria Coronariana/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Jejum , Proteínas Proto-Oncogênicas/metabolismo , Idoso , Glicemia/metabolismo , Doença da Artéria Coronariana/complicações , Diabetes Mellitus Tipo 2/complicações , Feminino , Teste de Tolerância a Glucose , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Triglicerídeos/metabolismo
20.
PLoS One ; 9(5): e97251, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24816905

RESUMO

BACKGROUND: The protein C pathway plays an important role in the maintenance of endothelial barrier function and in the inflammatory and coagulant processes that are characteristic of patients on dialysis. We investigated whether common single nucleotide variants (SNV) in genes encoding protein C pathway components were associated with all-cause 5 years mortality risk in dialysis patients. METHODS: Single nucleotides variants in the factor V gene (F5 rs6025; factor V Leiden), the thrombomodulin gene (THBD rs1042580), the protein C gene (PROC rs1799808 and 1799809) and the endothelial protein C receptor gene (PROCR rs867186, rs2069951, and rs2069952) were genotyped in 1070 dialysis patients from the NEtherlands COoperative Study on the Adequacy of Dialysis (NECOSAD) cohort) and in 1243 dialysis patients from the German 4D cohort. RESULTS: Factor V Leiden was associated with a 1.5-fold (95% CI 1.1-1.9) increased 5-year all-cause mortality risk and carriers of the AG/GG genotypes of the PROC rs1799809 had a 1.2-fold (95% CI 1.0-1.4) increased 5-year all-cause mortality risk. The other SNVs in THBD, PROC, and PROCR were not associated with 5-years mortality. CONCLUSION: Our study suggests that factor V Leiden and PROC rs1799809 contributes to an increased mortality risk in dialysis patients.


Assuntos
Fator V/genética , Polimorfismo de Nucleotídeo Único/genética , Proteína C/genética , Diálise Renal/mortalidade , Transdução de Sinais/genética , Antígenos CD/genética , Receptor de Proteína C Endotelial , Alemanha , Humanos , Países Baixos , Receptores de Superfície Celular/genética , Trombomodulina/genética
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