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AIMS: Gene therapies to induce cardiomyocyte (CM) cell cycle re-entry have shown a potential to treat subacute ischaemic heart failure (IHF) but have not been tested in the more relevant setting of chronic IHF. Our group recently showed that polycistronic non-integrating lentivirus encoding Cdk1/CyclinB1 and Cdk4/CyclinD1 (TNNT2-4Fpolycistronic-NIL) is effective in inducing CM cell cycle re-entry and ameliorating subacute IHF models and preventing the subsequent IHF-induced congestions in the liver, kidneys, and lungs in rats and pigs. Here, we aim to test the long-term efficacy of TNNT2-4Fpolycistronic-NIL in a rat model of chronic IHF, a setting that differs pathophysiologically from subacute IHF and has greater clinical relevance. METHODS AND RESULTS: Rats were subjected to a 2-h coronary occlusion followed by reperfusion; 4 weeks later, rats were injected intramyocardially with either TNNT2-4Fpolycistronic-NIL or LacZ-NIL. Four months post-viral injection, TNNT2-4Fpolycistronic-NIL-treated rats showed a significant reduction in scar size and a significant improvement in left ventricular (LV) systolic cardiac function but not in the LV dilatation associated with chronic IHF. A mitosis reporter system developed in our lab showed significant induction of CM mitotic activity in TNNT2-4Fpolycistronic-NIL-treated rats. CONCLUSION: This study demonstrates, for the first time, that TNNT2-4Fpolycistronic-NIL gene therapy induces CM cell cycle re-entry in chronic IHF and improves LV function, and that this salubrious effect is sustained for at least 4 months. Given the high prevalence of chronic IHF, these results have significant clinical implications for developing a novel treatment for this deadly disease.
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Insuficiencia Cardíaca , Isquemia Miocárdica , Ratas , Animales , Porcinos , Miocitos Cardíacos , Enfermedad Crónica , Terapia Genética , Ciclo CelularRESUMEN
Background Although the effects of psychological health and optimism have been extensively investigated, data from community-based cohorts assessing the association between psychological health and cardiovascular disease risk factors are sparse, and the concurrent relationship between subjective well-being and cardiovascular health has not been studied. Methods and Results The current cross-sectional study examined the association between well-being and cardiovascular risk factors among 719 individuals living in a middle- to low-income neighborhood. After adjusting for age, sex, race, body mass index, education, smoking status, and exercise status, we found that higher levels of well-being were significantly associated with lower odds of dyslipidemia (odds ratio [OR], 0.7 [95% CI, 0.55-0.85]) and hypertension (OR, 0.8 [95% CI, 0.63-0.92]). Greater well-being was also significantly associated with lower triglyceride levels (mean difference [Mdiff], 7.6 [-14.31 to -0.78]), very low-density lipoprotein (Mdiff, 0.9 [-1.71 to -0.16]), total cholesterol to high-density lipoprotein ratio (Mdiff, 3.9 [-6.07 to -1.73]), higher high-density lipoprotein levels (Mdiff, 1.6 [0.46-2.75]), and lower Framingham Risk Scores (Mdiff, -7.1% [-10.84% to -3.16%]). Well-being also moderated the association between age and arterial stiffness. The strongest association between arterial stiffness and age was found for those with the lowest well-being scores; there was no association between age and arterial stiffness at high levels of well-being. Conclusions In a community-based cohort, individuals reporting higher levels of well-being have lower odds of hypertension and dyslipidemia as well as lower rates of age-dependent increase in vascular stiffness. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03670524.
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Enfermedades Cardiovasculares , Dislipidemias , Hipertensión , Rigidez Vascular , Humanos , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Estudios Transversales , Dislipidemias/diagnóstico , Dislipidemias/epidemiología , Hipertensión/diagnóstico , Hipertensión/epidemiología , Lipoproteínas HDL , Factores de Riesgo , Masculino , FemeninoRESUMEN
Vinyl chloride (VC) is an organochlorine mainly used to manufacture its polymer polyvinyl chloride, which is extensively used in the manufacturing of consumer products. Recent studies suggest that chronic low dose VC exposure affects glucose homeostasis in high fat diet-fed mice. Our data suggest that even in the absence of high fat diet, exposure to VC (0.8 ppm, 6 h/day, 5 day/week, for 12 weeks) induces glucose intolerance (1.0 g/kg, i.p.) in male C57BL/6 mice. This was accompanied with the depletion of hepatic glutathione and a modest increase in lung interstitial macrophages. VC exposure did not affect the levels of circulating immune cells, endothelial progenitor cells, platelet-immune cell aggregates, and cytokines and chemokines. The acute challenge of VC-exposed mice with LPS did not affect lung immune cell composition or plasma IL-6. To examine the effect of VC exposure on vascular inflammation and atherosclerosis, LDL receptor-KO mice on C57BL/6 background maintained on western diet were exposed to VC for 12 weeks (0.8 ppm, 6 h/day, 5 day/week). Unlike the WT C57BL/6 mice, VC exposure did not affect glucose tolerance in the LDL receptor-KO mice. Plasma cytokines, lesion area in the aortic valve, and markers of lesional inflammation in VC-exposed LDL receptor-KO mice were comparable with the air-exposed controls. Collectively, despite impaired glucose tolerance and modest pulmonary inflammation, chronic low dose VC exposure does not affect surrogate markers of cardiovascular injury, LPS-induced acute inflammation in C57BL/6 mice, and chronic inflammation and atherosclerosis in the LDL receptor-KO mice.
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Enfermedades Cardiovasculares , Cloruro de Vinilo , Animales , Dieta Alta en Grasa , Hígado , Masculino , Ratones , Ratones Endogámicos C57BL , Cloruro de Vinilo/toxicidadRESUMEN
Occupational exposures to volatile organic compounds (VOCs) have been associated with numerous health complications including steatohepatitis and liver cancer. However, the potential impact of environmental/residential VOC exposures on liver health and function is largely unknown. To address this knowledge gap, the objective of this cross-sectional study is to investigate associations between VOCs and liver injury biomarkers in community residents. Subjects were recruited from six Louisville neighborhoods, and informed consent was obtained. Exposure biomarkers included 16 creatinine-adjusted urinary metabolites corresponding to 12 parent VOCs. Serological disease biomarkers measured included cytokertain-18 (K18 M65 and M30), liver enzymes, and direct bilirubin. Associations between exposure and disease biomarkers were assessed using generalized linear models. Smoking status was confirmed through urinary cotinine levels. The population comprised of approximately 60% females and 40% males; White persons accounted 78% of the population; with more nonsmokers (n = 413) than smokers (n = 250). When compared with nonsmokers, males (45%) and Black persons (26%) were more likely to be smokers. In the overall population, metabolites of acrolein, acrylonitrile, acrylamide, 1,3-butadiene, crotonaldehyde, styrene, and xylene were positively associated with alkaline phosphatase. These associations persisted in smokers, with the exception of crotonaldehyde, and addition of N,N-dimethylformamide and propylene oxide metabolites. Although no positive associations were observed for K18 M30, the benzene metabolite was positively associated with bilirubin, irrespective of smoking status. Taken together, the results demonstrated that selected VOCs were positively associated with liver injury biomarkers. These findings will enable better risk assessment and identification of populations vulnerable to liver disease.
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Compuestos Orgánicos Volátiles , Biomarcadores/orina , Estudios Transversales , Exposición a Riesgos Ambientales/efectos adversos , Femenino , Humanos , Hígado/metabolismo , Masculino , Compuestos Orgánicos Volátiles/metabolismoRESUMEN
Benzene is a ubiquitous environmental pollutant. Recent population-based studies suggest that benzene exposure is associated with an increased risk for cardiovascular disease. However, it is unclear whether benzene exposure by itself is sufficient to induce cardiovascular toxicity. We examined the effects of benzene inhalation (50 ppm, 6 h/day, 5 days/week, 6 weeks) or HEPA-filtered air exposure on the biomarkers of cardiovascular toxicity in male C57BL/6J mice. Benzene inhalation significantly increased the biomarkers of endothelial activation and injury including endothelial microparticles, activated endothelial microparticles, endothelial progenitor cell microparticles, lung endothelial microparticles, and activated lung and endothelial microparticles while having no effect on circulating levels of endothelial adhesion molecules, endothelial selectins, and biomarkers of angiogenesis. To understand how benzene may induce endothelial injury, we exposed human aortic endothelial cells to benzene metabolites. Of the metabolites tested, trans,trans-mucondialdehyde (10 µM, 18h) was the most toxic. It induced caspases-3, -7 and -9 (intrinsic pathway) activation and enhanced microparticle formation by 2.4-fold. Levels of platelet-leukocyte aggregates, platelet macroparticles, and a proportion of CD4+ and CD8+ T-cells were also significantly elevated in the blood of the benzene-exposed mice. We also found that benzene exposure increased the transcription of genes associated with endothelial cell and platelet activation in the liver; and induced inflammatory genes and suppressed cytochrome P450s in the lungs and the liver. Together, these data suggest that benzene exposure induces endothelial injury, enhances platelet activation and inflammatory processes; and circulatory levels of endothelial cell and platelet-derived microparticles and platelet-leukocyte aggregates are excellent biomarkers of cardiovascular toxicity of benzene.
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Benceno/toxicidad , Enfermedades Cardiovasculares/inducido químicamente , Sistema Cardiovascular/efectos de los fármacos , Animales , Enfermedades Asintomáticas , Benceno/administración & dosificación , Biomarcadores/sangre , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Plaquetas/patología , Cardiotoxicidad , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/patología , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/patología , Micropartículas Derivadas de Células/efectos de los fármacos , Micropartículas Derivadas de Células/metabolismo , Micropartículas Derivadas de Células/patología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Células Endoteliales/patología , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patología , Exposición por Inhalación , Leucocitos/efectos de los fármacos , Leucocitos/metabolismo , Leucocitos/patología , Masculino , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: The popularity of electronic cigarettes (E-cigarettes) has risen considerably. Several studies have suggested that nicotine may affect insulin resistance, however, the impact of E-cigarette exposure on insulin resistance, an early measure of cardiometabolic risk, is not known. METHODS AND RESULTS: Using experimental animals and human data obtained from 3,989 participants of the United States National Health and Nutrition Examination Survey (NHANES), respectively, we assessed the association between E-cigarette and conventional cigarette exposures and insulin resistance, as modelled using the homeostatic model assessment of insulin resistance (HOMA-IR) and glucose tolerance tests (GTT). C57BL6/J mice (on standard chow diet) exposed to E-cigarette aerosol or mainstream cigarette smoke (MCS) for 12 weeks showed HOMA-IR and GTT levels comparable with filtered air-exposed controls. In the NHANES cohort, there was no significant association between defined tobacco product use categories (non-users; sole E-cigarette users; cigarette smokers and dual users) and insulin resistance. Compared with non-users of e-cigarettes/conventional cigarettes, sole E-cigarette users showed no significant difference in HOMA-IR or GTT levels following adjustment for age, sex, race, physical activity, alcohol use and BMI. CONCLUSION: E-cigarettes do not appear to be linked with insulin resistance. Our findings may inform future studies assessing potential cardiometabolic harms associated with E-cigarette use.