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2.
JAMA Netw Open ; 3(10): e2018534, 2020 10 01.
Article in English | MEDLINE | ID: mdl-33006618

ABSTRACT

Importance: Children with food allergies may develop asthma or recurrent wheeze. Objective: To evaluate whether asthma or recurrent wheeze among children were changed by avoiding supplementing breastfeeding (BF) with cow's milk formula (CMF) in the first 3 days of life. Design, Setting, and Participants: This randomized, unmasked, clinical trial was conducted at 1 university hospital in Japan beginning October 2013 with follow-up examinations occurring until January 2020. A total of 312 newborns at risk for atopy were randomized and assigned to either BF with or without amino acid-based elemental formula (EF) or BF with CMF, with follow-up examinations for participants showing signs of atopy conducted at 24 months. Follow-up examinations ran through January 2020. Interventions: Immediately after birth, newborns were randomly assigned (1:1 ratio) to either breastfeeding with or without amino acid-based elemental formula for at least the first 3 days of life (no CMF group) or breastfeeding supplemented with CMF (≥5 mL/d) from the first day of life to 5 months of age (CMF group). Main Outcomes and Measures: Asthma or recurrent wheeze diagnosed by the pediatric allergy specialists of this trial; subgroups were stratified by serum levels of 25-hydroxyvitamin D and IgE. Results: Of 312 infants (156 [50.0%] randomized to the no CMF group), 302 (96.8%) were followed up at their second birthday: 77 of 151 (51.0%) in the no CMF group and 81 of 151 (53.6%) in the CMF group underwent extended follow-up because of having atopic conditions. Asthma or recurrent wheeze developed in 15 (9.9%) of the children in the no CMF group, significantly less than the children in the CMF group (27 [17.9%]; risk difference, -0.079; 95% CI, -0.157 to -0.002). In participants with vitamin D levels above the median at 5 months of age, asthma or recurrent wheeze developled in 5 (6.4%) children in the no CMF group, significantly less than in the children in the CMF group (17 [24.6%]; risk difference, -0.182; 95% CI, -0.298 to -0.067; P for interaction = .04). In the highest quartile group of total IgE at age 24 months, asthma or recurrent wheeze developed in 2 children (5.3%) in the no CMF group, significantly less than the children in the CMF group (14 [43.8%]; risk difference, -0.385; 95% CI, -0.571 to -0.199; P for interaction = .004). Conclusions and Relevance: The findings of this study suggest that avoiding CMF supplementation in the first 3 days of life has the potential to reduce the risk of asthma or recurrent wheeze in young children, especially among those with high vitamin D or high IgE levels. Trial Registration: umin.ac.jp/ctr Identifier: UMIN000011577.


Subject(s)
Asthma/etiology , Asthma/prevention & control , Asthma/physiopathology , Infant Formula/adverse effects , Milk Hypersensitivity/physiopathology , Milk/adverse effects , Respiratory Sounds/physiopathology , Animals , Cattle , Female , Follow-Up Studies , Humans , Infant , Infant, Newborn , Japan , Male
3.
PLoS One ; 15(4): e0231905, 2020.
Article in English | MEDLINE | ID: mdl-32315372

ABSTRACT

Myocardial fibrosis is often associated with cardiac hypertrophy; indeed, fibrosis is one of the most critical factors affecting prognosis. We aimed to identify the molecules involved in promoting fibrosis under hypertrophic stimuli. We previously established a rat model of cardiac hypertrophy by pulmonary artery banding, in which approximately half of the animals developed fibrosis in the right ventricle. Here, we first comprehensively analyzed mRNA expression in the right ventricle with or without fibrosis in pulmonary artery banding model rats by DNA microarray analysis (GSE141650 at NCBI GEO). The expression levels of 19 genes were up-regulated more than 1.5-fold in fibrotic hearts compared with non-fibrotic hearts. Among them, fibrosis growth factor (FGF) 23 showed one of the biggest increases in expression. Real-time PCR analysis also revealed that, among the FGF receptor (FGFR) family, FGFR1 was highly expressed in fibrotic hearts. We then found that FGF23 was expressed predominantly in cardiomyocytes, while FGFR1 was predominantly expressed in fibroblasts in the rat ventricle. Next, we added FGF23 and transforming growth factor (TGF)-ß1 (10-50 ng/mL of each) to isolated fibroblasts from normal adult rat ventricles and cultured them for three days. While FGF23 itself did not directly affect the expression levels of any fibrosis-related mRNAs, FGF23 enhanced the effect of TGF-ß1 on increasing the expression levels of α-smooth muscle actin (α-SMA) mRNA. This increase in xx-SMA mRNA levels due to the combination of TGF-ß1 and FGF23 was attenuated by the inhibition of FGFR1 or the knockdown of FGFR1 in fibroblasts. Thus, FGF23 synergistically promoted the activation of fibroblasts with TGF-ß1, transforming fibroblasts into myofibroblasts via FGFR1. Thus, we identified FGF23 as a paracrine factor secreted from cardiomyocytes to promote cardiac fibrosis under conditions in which TGF-ß1 is activated. FGF23 could be a possible target to prevent fibrosis following myocardial hypertrophy.


Subject(s)
Fibroblast Growth Factors/pharmacology , Heart Diseases/pathology , Transforming Growth Factor beta1/pharmacology , Up-Regulation/drug effects , Actins/genetics , Actins/metabolism , Animals , Cells, Cultured , Disease Models, Animal , Fibroblast Growth Factor-23 , Fibroblast Growth Factors/genetics , Fibroblast Growth Factors/metabolism , Fibroblasts/cytology , Fibroblasts/metabolism , Fibrosis , Heart Diseases/metabolism , Male , Myocytes, Cardiac/cytology , Myocytes, Cardiac/metabolism , Pyrroles/pharmacology , Rats , Rats, Sprague-Dawley , Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors , Receptor, Fibroblast Growth Factor, Type 1/metabolism
4.
JAMA Pediatr ; 173(12): 1137-1145, 2019 12 01.
Article in English | MEDLINE | ID: mdl-31633778

ABSTRACT

Importance: Cow's milk formula (CMF) is used to supplement breastfeeding (BF) at birth without clear clinical evidence to support the practice. Objective: To determine whether avoiding supplementation with CMF at birth can decrease risks of sensitization to cow's milk protein and/or clinical food allergy, including cow's milk allergy (CMA), overall and in subgroups stratified by 25-hydroxyvitamin D (25[OH]D) levels. Design, Setting, and Participants: The Atopy Induced by Breastfeeding or Cow's Milk Formula (ABC) trial, a randomized, nonblinded clinical trial, began enrollment October 1, 2013, and completed follow-up May 31, 2018, at a single university hospital in Japan. Participants included 330 newborns at risk for atopy; of these, 312 were included in the analysis. Data were analyzed from September 1 through October 31, 2018. Interventions: Immediately after birth, newborns were randomized (1:1 ratio) to BF with or without amino acid-based elemental formula (EF) for at least the first 3 days of life (BF/EF group) or BF supplemented with CMF (≥5 mL/d) from the first day of life to 5 months of age (BF plus CMF group). Main Outcomes and Measures: The primary outcome was sensitization to cow's milk (IgE level, ≥0.35 allergen units [UA]/mL) at the infant's second birthday. Secondary outcomes were immediate and anaphylactic types of food allergy, including CMA, diagnosed by oral food challenge test or triggered by food ingestion, with food-specific IgE levels of at least 0.35 UA/mL. Subgroup analysis was prespecified by tertiles of serum 25(OH)D levels at 5 months of age. Results: Of the 312 infants included in the analysis (160 female [51.3%] and 152 male [48.7%]), 151 of 156 (96.8%) in the BF/EF and BF plus CMF groups were followed up until their second birthday. The primary outcome occurred in 24 infants (16.8%) in the BF/EF group, which was significantly fewer than the 46 infants (32.2%) in the BF plus CMF group (relative risk [RR], 0.52; 95% CI, 0.34-0.81). The middle tertile of the 25(OH)D subgroup, but not the low and high tertiles, had a significant interaction with the intervention (RR, 0.19; 95% CI, 0.07-0.50; P = .02). The prevalence of food allergy at the second birthday was significantly lower in the BF/EF than in the BF plus CMF groups for immediate (4 [2.6%] vs 20 [13.2%]; RR, 0.20; 95% CI, 0.07-0.57) and anaphylactic (1 [0.7%] vs 13 [8.6%]; RR, 0.08; 95% CI, 0.01-0.58) types. Conclusions and Relevance: The evidence suggests that sensitization to cow's milk and food allergy, including CMA and anaphylaxis, are primarily preventable by avoiding CMF supplementation for at least the first 3 days of life. Trial Registration: http://umin.ac.jp Identifier: UMIN000011577.


Subject(s)
Dietary Supplements , Food Hypersensitivity/prevention & control , Infant Formula/adverse effects , Milk Hypersensitivity/prevention & control , Primary Prevention/methods , Adult , Breast Feeding , Female , Follow-Up Studies , Food Hypersensitivity/epidemiology , Humans , Infant, Newborn , Japan/epidemiology , Male , Milk Hypersensitivity/epidemiology , Prevalence , Retrospective Studies
5.
J Thorac Cardiovasc Surg ; 154(5): 1742-1753.e8, 2017 11.
Article in English | MEDLINE | ID: mdl-28755882

ABSTRACT

OBJECTIVE: A rat model of left atrial stenosis-associated pulmonary hypertension due to left heart diseases was prepared to elucidate its mechanism. METHODS: Five-week-old Sprague-Dawley rats were randomly divided into 2 groups: left atrial stenosis and sham-operated control. Echocardiography was performed 2, 4, 6, and 10 weeks after surgery, and cardiac catheterization and organ excision were subsequently performed at 10 weeks after surgery. RESULTS: Left ventricular inflow velocity, measured by echocardiography, significantly increased in the left atrial stenosis group compared with that in the sham-operated control group (2.2 m/s, interquartile range [IQR], 1.9-2.2 and 1.1 m/s, IQR, 1.1-1.2, P < .01), and the right ventricular pressure-to-left ventricular systolic pressure ratio significantly increased in the left atrial stenosis group compared with the sham-operated control group (0.52, IQR, 0.54-0.60 and 0.22, IQR, 0.15-0.27, P < .01). The right ventricular weight divided by body weight was significantly greater in the left atrial stenosis group than in the sham-operated control group (0.54 mg/g, IQR, 0.50-0.59 and 0.39 mg/g, IQR, 0.38-0.43, P < .01). Histologic examination revealed medial hypertrophy of the pulmonary vein was thickened by 1.6 times in the left atrial stenosis group compared with the sham-operated control group. DNA microarray analysis and real-time polymerase chain reaction revealed that transforming growth factor-ß mRNA was significantly elevated in the left atrial stenosis group. The protein levels of transforming growth factor-ß and endothelin-1 were increased in the lung of the left atrial stenosis group by Western blot analyses. CONCLUSIONS: We successfully established a novel, feasible rat model of pulmonary hypertension due to left heart diseases by generating left atrial stenosis. Although pulmonary hypertension was moderate, the pulmonary hypertension due to left heart diseases model rats demonstrated characteristic intrapulmonary venous arterialization and should be used to further investigate the mechanism of pulmonary hypertension due to left heart diseases.


Subject(s)
Heart Atria , Heart Ventricles , Hypertension, Pulmonary , Pulmonary Veins , Animals , Constriction, Pathologic , Disease Models, Animal , Echocardiography/methods , Heart Atria/diagnostic imaging , Heart Atria/pathology , Heart Atria/physiopathology , Heart Ventricles/diagnostic imaging , Heart Ventricles/physiopathology , Hypertension, Pulmonary/blood , Hypertension, Pulmonary/diagnosis , Hypertension, Pulmonary/physiopathology , Pulmonary Circulation , Pulmonary Veins/diagnostic imaging , Pulmonary Veins/pathology , Pulmonary Veins/physiopathology , Rats , Rats, Sprague-Dawley , Ventricular Dysfunction, Left/diagnostic imaging
6.
PLoS One ; 12(1): e0169564, 2017.
Article in English | MEDLINE | ID: mdl-28068381

ABSTRACT

Interstitial myocardial fibrosis is one of the factors responsible for dysfunction of the heart. However, how interstitial fibrosis affects cardiac function and excitation-contraction coupling (E-C coupling) has not yet been clarified. We developed an animal model of right ventricular (RV) hypertrophy with fibrosis by pulmonary artery (PA) banding in rats. Two, four, and six weeks after the PA-banding operation, the tension and intracellular Ca2+ concentration of RV papillary muscles were simultaneously measured (n = 33). The PA-banding rats were clearly divided into two groups by the presence or absence of apparent interstitial fibrosis in the papillary muscles: F+ or F- group, respectively. The papillary muscle diameter and size of myocytes were almost identical between F+ and F-, although the RV free wall weight was heavier in F+ than in F-. F+ papillary muscles exhibited higher stiffness, lower active tension, and lower Ca2+ responsiveness compared with Sham and F- papillary muscles. In addition, we found that the time to peak Ca2+ had the highest correlation coefficient to percent of fibrosis among other parameters, such as RV weight and active tension of papillary muscles. The phosphorylation level of troponin I in F+ was significantly higher than that in Sham and F-, which supports the idea of lower Ca2+ responsiveness in F+. We also found that connexin 43 in F+ was sparse and disorganized in the intercalated disk area where interstitial fibrosis strongly developed. In the present study, the RV papillary muscles obtained from the PA-banding rats enabled us to directly investigate the relationship between fibrosis and cardiac dysfunction, the impairment of E-C coupling in particular. Our results suggest that interstitial fibrosis worsens cardiac function due to 1) the decrease in Ca2+ responsiveness and 2) the asynchronous activation of each cardiac myocyte in the fibrotic preparation due to sparse cell-to-cell communication.


Subject(s)
Excitation Contraction Coupling , Hypertrophy, Right Ventricular/pathology , Hypertrophy, Right Ventricular/physiopathology , Pulmonary Artery/physiopathology , Aequorin/metabolism , Animals , Biomarkers , Calcium/metabolism , Connexin 43/genetics , Connexin 43/metabolism , Fibrosis , Gene Expression , Heart Failure/pathology , Heart Failure/physiopathology , Hypertrophy, Right Ventricular/genetics , Hypertrophy, Right Ventricular/metabolism , Male , Membrane Potentials , Papillary Muscles/pathology , Papillary Muscles/physiopathology , Phosphorylation , Rats , Troponin I/metabolism
7.
PLoS One ; 11(2): e0148666, 2016.
Article in English | MEDLINE | ID: mdl-26863419

ABSTRACT

BACKGROUND: Hepatic fibrosis progresses with right heart failure, and becomes cardiac cirrhosis in a severe case. Although its causal factor still remains unclear. Here we evaluated the progression of hepatic fibrosis using a pulmonary artery banding (PAB)-induced right heart failure model and investigated whether cardiac output (CO) is responsible for the progression of hepatic fibrosis. METHODS AND RESULTS: Five-week-old Sprague-Dawley rats divided into the PAB and sham-operated control groups. After 4 weeks from operation, we measured CO by echocardiography, and hepatic fibrosis ratio by pathological examination using a color analyzer. In the PAB group, CO was significantly lower by 48% than that in the control group (78.2±27.6 and 150.1±31.2 ml/min, P<0.01). Hepatic fibrosis ratio and serum hyaluronic acid, an index of hepatic fibrosis, were significantly increased in the PAB group than those in the control group (7.8±1.7 and 1.0±0.2%, P<0.01, 76.2±27.5 and 32.7±7.5 ng/ml, P<0.01). Notably, the degree of hepatic fibrosis significantly correlated a decrease in CO. Immunohistological analysis revealed that hepatic stellate cells were markedly activated in hypoxic areas, and HIF-1α positive hepatic cells were increased in the PAB group. Furthermore, by real-time PCR analyses, transcripts of profibrotic and fibrotic factors (TGF-ß1, CTGF, procollargen I, procollargen III, MMP 2, MMP 9, TIMP 1, TIMP 2) were significantly increased in the PAB group. In addition, western blot analyses revealed that the protein level of HIF-1α was significantly increased in the PAB group than that in the control group (2.31±0.84 and 1.0±0.18 arbitrary units, P<0.05). CONCLUSIONS: Our study demonstrated that low CO and tissue hypoxia were responsible for hepatic fibrosis in right failure heart model rats.


Subject(s)
Cardiac Output, Low/complications , Heart Failure/complications , Liver Cirrhosis/etiology , Animals , Cardiac Output, Low/blood , Cell Hypoxia , Disease Models, Animal , Gene Expression , Heart Failure/blood , Hyaluronic Acid/blood , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Liver/pathology , Liver Cirrhosis/blood , Male , Myofibroblasts/pathology , Rats, Sprague-Dawley
8.
J Mol Cell Cardiol ; 63: 155-64, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23920331

ABSTRACT

Beta adrenergic receptor (ß-AR) subtypes act through diverse signaling cascades to modulate cardiac function and remodeling. Previous in vitro studies suggest that ß1-AR signaling is cardiotoxic whereas ß2-AR signaling is cardioprotective, and may be the case during ischemia/reperfusion in vivo. The objective of this study was to assess whether ß2-ARs also play a cardioprotective role in the pathogenesis of non-ischemic forms of cardiomyopathy. To dissect the role of ß1 vs ß2-ARs in modulating MLP (Muscle LIM Protein) cardiomyopathy, we crossbred MLP-/- with ß1-/- or ß2-/- mice. Deletion of the ß2-AR improved survival, cardiac function, exercise capacity and myocyte shortening; by contrast haploinsufficency of the ß1-AR reduced survival. Pathologic changes in Ca(2+) handling were reversed in the absence of ß2-ARs: peak Ca(2+) and SR Ca(2+) were decreased in MLP-/- and ß1+/-/MLP-/- but restored in ß2-/-MLP-/-. These changes were associated with reversal of alterations in troponin I and phospholamban phosphorylation. Gi inhibition increased peak and baseline Ca(2+), recapitulating changes observed in the ß2-/-/MLP-/-. The L-type Ca(2+) blocker verapamil significantly decreased cardiac function in ß2-/-MLP-/- vs WT. We next tested if the protective effects of ß2-AR ablation were unique to the MLP model using TAC-induced heart failure. Similar to MLP, ß2-/- mice demonstrated delayed progression of heart failure with restoration of myocyte shortening and peak Ca(2+) and Ca(2+) release. Deletion of ß2-ARs prevents the development of MLP-/- cardiomyopathy via positive modulation of Ca(2+) due to removal of inhibitory Gi signaling and increased phosphorylation of troponin I and phospholamban. Similar effects were seen after TAC. Unlike previous models where ß2-ARs were found to be cardioprotective, in these two models, ß2-AR signaling appears to be deleterious, potentially through negative regulation of Ca(2+) dynamics.


Subject(s)
Cardiomyopathies/genetics , Gene Deletion , Receptors, Adrenergic, beta-2/genetics , Adrenergic beta-2 Receptor Antagonists/pharmacology , Animals , Calcium/metabolism , Cardiomyopathies/metabolism , Cardiomyopathies/mortality , Cardiomyopathies/pathology , Disease Models, Animal , Disease Progression , Excitation Contraction Coupling/drug effects , Excitation Contraction Coupling/genetics , Heart Failure/genetics , Heart Failure/metabolism , Heart Failure/mortality , Heart Failure/pathology , LIM Domain Proteins/genetics , LIM Domain Proteins/metabolism , Mice , Mice, Knockout , Muscle Proteins/genetics , Muscle Proteins/metabolism , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Receptors, Adrenergic, beta-2/metabolism
9.
Am J Physiol Heart Circ Physiol ; 301(4): H1461-70, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21705675

ABSTRACT

In isolated myocytes, hypertrophy induced by norepinephrine is mediated via α(1)-adrenergic receptors (ARs) and not ß-ARs. However, mice with deletions of both major cardiac α(1)-ARs still develop hypertrophy in response to pressure overload. Our purpose was to better define the role of ß-AR subtypes in regulating cardiac hypertrophy in vivo, important given the widespread clinical use of ß-AR antagonists and the likelihood that patients treated with these agents could develop conditions of further afterload stress. Mice with deletions of ß(1), ß(2), or both ß(1)- and ß(2)-ARs were subjected to transverse aortic constriction (TAC). After 3 wk, ß(1)(-/-) showed a 21% increase in heart to body weight vs. sham controls, similar to wild type, whereas ß(2)(-/-) developed exaggerated (49% increase) hypertrophy. Only when both ß-ARs were ablated (ß(1)ß(2)(-/-)) was hypertrophy totally abolished. Cardiac function was preserved in all genotypes. Several known inhibitors of cardiac hypertrophy (FK506 binding protein 5, thioredoxin interacting protein, and S100A9) were upregulated in ß(1)ß(2)(-/-) compared with the other genotypes, whereas transforming growth factor-ß(2), a positive mediator of hypertrophy was upregulated in all genotypes except the ß(1)ß(2)(-/-). In contrast to recent reports suggesting that angiogenesis plays a critical role in regulating cardiac hypertrophy-induced heart failure, we found no evidence that angiogenesis or its regulators (VEGF, Hif1α, and p53) play a role in compensated cardiac hypertrophy. Pressure overload hypertrophy in vivo is dependent on a coordination of signaling through both ß(1)- and ß(2)-ARs, mediated through several key cardiac remodeling pathways. Angiogenesis is not a prerequisite for compensated cardiac hypertrophy.


Subject(s)
Cardiomegaly/physiopathology , Heart/physiopathology , Hypertension/physiopathology , Receptors, Adrenergic, beta/physiology , Angiogenesis Inducing Agents/metabolism , Animals , Aorta, Thoracic/physiology , Blood Pressure/physiology , Cardiomegaly/etiology , Cardiomegaly/genetics , Constriction, Pathologic/physiopathology , Electrocardiography , Genome-Wide Association Study , Heart Failure/etiology , Heart Failure/physiopathology , Hypertension/complications , Hypertension/genetics , Male , Mice , Mice, Knockout , Microarray Analysis , Paraffin Embedding , RNA/biosynthesis , RNA/genetics , Receptors, Adrenergic, beta/genetics , Receptors, Adrenergic, beta-1/genetics , Receptors, Adrenergic, beta-1/physiology , Receptors, Adrenergic, beta-2/genetics , Receptors, Adrenergic, beta-2/physiology , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/genetics , Signal Transduction/physiology
10.
Mol Genet Metab ; 100(1): 14-9, 2010 May.
Article in English | MEDLINE | ID: mdl-20202878

ABSTRACT

We report 4 cases of late onset glycogen storage disease type II (GSD II) or Pompe disease (OMIM #232300), under enzyme replacement therapy (ERT) with recombinant human acid alpha glucosidase (rh-GAA, OMIM *606800). In these 4 cases, we focused on the case of a 28-years-old man, whose condition at the ERT starting was the worst and resulted in poor prognosis. The autopsy was done under his family's permission, and revealed severe accumulation of glycogen in his muscle, especially diaphragm or iliopsoas, and pulmonary veno-occlusive disease (PVOD) which resulted in severe pulmonary hypertension (PH). This is the first report of PVOD as the cause of PH in Pompe disease. We studied this case comparing to another 3 cases of late onset Pompe disease under the same course of ERT in our hospital, and the average data of the group of late onset Pompe disease with severe pulmonary insufficiency receiving ERT, supposed that low score of the body mass index (BMI) on the baseline, the presence of specific genotype (p.R600C), and signs of pulmonary dysfunction suggesting PH (tachypnea, ultrasound cardiography data) were factors that influenced the prognosis. For a better prognosis in the late onset Pompe disease, an early diagnosis for the early start of ERT before the onset of respiratory failure should be important, and the deliberate management and care should be needed even after the ERT start, especially for severe cases including pulmonary dysfunction.


Subject(s)
Enzyme Replacement Therapy , Glycogen Storage Disease Type II/enzymology , Glycogen Storage Disease Type II/therapy , alpha-Glucosidases/therapeutic use , Adolescent , Adult , Autopsy , Child, Preschool , Fatal Outcome , Female , Glycogen Storage Disease Type II/complications , Humans , Hypertension, Pulmonary/etiology , Male , Prognosis , Pulmonary Veno-Occlusive Disease/complications
11.
Am J Physiol Heart Circ Physiol ; 295(3): H1351-H1368, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18586894

ABSTRACT

Right ventricular (RV) dysfunction is a common long-term complication in patients after the repair of congenital heart disease. Previous investigators have examined the cellular and molecular mechanisms of left ventricular (LV) remodeling, but little is known about the stressed RV. Our purpose was to provide a detailed physiological characterization of a model of RV hypertrophy and failure, including RV-LV interaction, and to compare gene alterations between afterloaded RV versus LV. Pulmonary artery constriction was performed in 86 mice. Mice with mild and moderate pulmonary stenosis (PS) developed stable hypertrophy without decompensation. Mice with severe PS developed edema, decreased RV function, and high mortality. Tissue Doppler imaging demonstrated septal dyssynchrony and deleterious RV-LV interaction in the severe PS group. Microarray analysis showed 196 genes with increased expression and 1,114 with decreased expression. Several transcripts were differentially increased in the afterloaded RV but not in the afterloaded LV, including clusterin, neuroblastoma suppression of tumorigenicity 1, Dkk3, Sfrp2, formin binding protein, annexin A7, and lysyl oxidase. We have characterized a murine model of RV hypertrophy and failure, providing a platform for studying the physiological and molecular events of RV remodeling. Although the molecular responses of the RV and LV to afterload stress are mostly concordant, there are several key differences, which may represent targets for RV failure-specific therapy.


Subject(s)
Pulmonary Valve Stenosis/metabolism , Pulmonary Valve Stenosis/physiopathology , Ventricular Function, Right/physiology , Ventricular Remodeling/physiology , Animals , Echocardiography , Edema/pathology , Gene Expression/physiology , Heart Failure/diagnostic imaging , Heart Failure/physiopathology , Laser-Doppler Flowmetry , Male , Mice , Oligonucleotide Array Sequence Analysis , Organ Size/physiology , Pulmonary Valve Stenosis/genetics , Survival Analysis , Tetralogy of Fallot/physiopathology , Ventricular Remodeling/genetics
12.
J Clin Invest ; 118(5): 1846-57, 2008 May.
Article in English | MEDLINE | ID: mdl-18382765

ABSTRACT

Loss-of-function mutations in bone morphogenetic protein receptor II (BMP-RII) are linked to pulmonary arterial hypertension (PAH); the ligand for BMP-RII, BMP-2, is a negative regulator of SMC growth. Here, we report an interplay between PPARgamma and its transcriptional target apoE downstream of BMP-2 signaling. BMP-2/BMP-RII signaling prevented PDGF-BB-induced proliferation of human and murine pulmonary artery SMCs (PASMCs) by decreasing nuclear phospho-ERK and inducing DNA binding of PPARgamma that is independent of Smad1/5/8 phosphorylation. Both BMP-2 and a PPARgamma agonist stimulated production and secretion of apoE by SMCs. Using a variety of methods, including short hairpin RNAi in human PASMCs, PAH patient-derived BMP-RII mutant PASMCs, a PPARgamma antagonist, and PASMCs isolated from PPARgamma- and apoE-deficient mice, we demonstrated that the antiproliferative effect of BMP-2 was BMP-RII, PPARgamma, and apoE dependent. Furthermore, we created mice with targeted deletion of PPARgamma in SMCs and showed that they spontaneously developed PAH, as indicated by elevated RV systolic pressure, RV hypertrophy, and increased muscularization of the distal pulmonary arteries. Thus, PPARgamma-mediated events could protect against PAH, and PPARgamma agonists may reverse PAH in patients with or without BMP-RII dysfunction.


Subject(s)
Apolipoproteins E/metabolism , Bone Morphogenetic Protein Receptors, Type II/metabolism , Bone Morphogenetic Proteins/metabolism , Hypertension, Pulmonary/metabolism , Myocytes, Smooth Muscle/metabolism , PPAR gamma/metabolism , Transforming Growth Factor beta/metabolism , Animals , Apolipoproteins E/genetics , Becaplermin , Bone Morphogenetic Protein 2 , Bone Morphogenetic Protein Receptors, Type II/genetics , Bone Morphogenetic Proteins/genetics , Cells, Cultured , Extracellular Signal-Regulated MAP Kinases/genetics , Extracellular Signal-Regulated MAP Kinases/metabolism , Hemodynamics , Humans , Hypertension, Pulmonary/physiopathology , Hypoglycemic Agents/metabolism , Mice , Mice, Knockout , Mice, Transgenic , Muscle, Smooth, Vascular/cytology , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/cytology , PPAR gamma/genetics , Platelet-Derived Growth Factor/metabolism , Proto-Oncogene Proteins c-sis , RNA Interference , Rosiglitazone , Signal Transduction/physiology , Thiazolidinediones/metabolism , Transforming Growth Factor beta/genetics
13.
Circ Res ; 102(3): 380-8, 2008 Feb 15.
Article in English | MEDLINE | ID: mdl-18079409

ABSTRACT

Vascular expression of bone morphogenetic type IA receptor (Bmpr1a) is reduced in lungs of patients with pulmonary arterial hypertension, but the significance of this observation is poorly understood. To elucidate the role of Bmpr1a in the vascular pathology of pulmonary arterial hypertension and associated right ventricular (RV) dysfunction, we deleted Bmpr1a in vascular smooth muscle cells and in cardiac myocytes in mice using the SM22alpha;TRE-Cre/LoxP;R26R system. The LacZ distribution reflected patchy deletion of Bmpr1a in the lung vessels, aorta, and heart of SM22alpha;TRE-Cre;R26R;Bmpr1a(flox/+) and flox/flox mutants. This reduction in BMPR-IA expression was confirmed by Western immunoblot and immunohistochemistry in the flox/flox group. This did not affect pulmonary vasoreactivity to acute hypoxia (10% O2) or the increase in RV systolic pressure and RV hypertrophy following 3 weeks in chronic hypoxia. However, both SM22alpha;TRE-Cre;R26R;Bmpr1a(flox/+) and flox/flox mutant mice had fewer muscularized distal pulmonary arteries and attenuated loss of peripheral pulmonary arteries compared with age-matched control littermates in hypoxia. When Bmpr1a expression was reduced by short interference RNA in cultured pulmonary arterial smooth muscle cells, serum-induced proliferation was attenuated explaining decreased hypoxia-mediated muscularization of distal vessels. When Bmpr1a was reduced in cultured microvascular pericytes by short interference RNA, resistance to apoptosis was observed and this could account for protection against hypoxia-mediated vessel loss. The similar elevation in RV systolic pressure and RV hypertrophy, despite the attenuated remodeling with chronic hypoxia in the flox/flox mutants versus controls, was not a function of elevated left ventricular end diastolic pressure but was associated with increased periadventitial deposition of elastin and collagen, potentially influencing vascular stiffness.


Subject(s)
Bone Morphogenetic Protein Receptors, Type I/metabolism , Lung/blood supply , Microfilament Proteins/metabolism , Muscle Proteins/metabolism , Myocardial Contraction , Myocardium/metabolism , Neovascularization, Pathologic/metabolism , Animals , Aorta/metabolism , Aorta/pathology , Arteries/metabolism , Arteries/pathology , Bone Morphogenetic Protein Receptors, Type I/genetics , Cells, Cultured , Collagen/biosynthesis , Collagen/genetics , Coronary Circulation/genetics , Elastin/biosynthesis , Elastin/genetics , Humans , Hypertension, Pulmonary/genetics , Hypertension, Pulmonary/metabolism , Hypertension, Pulmonary/pathology , Hypoxia/genetics , Hypoxia/metabolism , Hypoxia/pathology , Lung/metabolism , Lung/pathology , Mice , Mice, Knockout , Microfilament Proteins/genetics , Muscle Proteins/genetics , Myocardial Contraction/genetics , Myocardium/pathology , Myocytes, Smooth Muscle/metabolism , Myocytes, Smooth Muscle/pathology , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/pathology
14.
Circ Cardiovasc Imaging ; 1(1): 6-13, 2008 Jul.
Article in English | MEDLINE | ID: mdl-19808509

ABSTRACT

BACKGROUND: We tested the hypothesis that multimodality imaging of mouse embryonic stem cells (mESCs) provides accurate assessment of cellular location, viability, and restorative potential after transplantation into different zones of myocardial infarction. METHODS AND RESULTS: Mice underwent left anterior descending artery ligation followed by transplantation of dual-labeled mESCs with superparamagnetic iron oxide and luciferase via direct injection into 3 different zones of myocardial infarction: intra-infarction, peri-infarction, and normal (remote). One day after transplantation, magnetic resonance imaging enabled assessment of the precise anatomic locations of mESCs. Bioluminescence imaging allowed longitudinal analysis of cell viability through detection of luciferase activity. Subsequent evaluation of myocardial regeneration and functional restoration was performed by echocardiography and pressure-volume loop analysis. Using 16-segment analysis, we demonstrated precise localization of dual-labeled mESCs. A strong correlation between histology and magnetic resonance imaging was established (r=0.962, P=0.002). Bioluminescent imaging data demonstrated that cell viability in the remote group was significantly higher than in other groups. Echocardiography and pressure-volume loop analysis revealed improved functional restoration in animals treated with mESCs, although myocardial regeneration was not observed. CONCLUSIONS: Multimodality evaluation of mESC engraftment in the heterogeneous tissue of myocardial infarction is possible. Magnetic resonance imaging demonstrated accurate anatomic localization of dual-labeled mESCs. Bioluminescent imaging enabled assessment of variable viability of mESCs transplanted into the infarcted myocardium. Echocardiography and pressure-volume loop analysis validated the restorative potential of mESCs. Although mESCs transplanted into the remote zone demonstrated the highest viability, precise delivery of mESCs into the peri-infarction region might be equally critical in restoring the injured myocardium.


Subject(s)
Embryonic Stem Cells/transplantation , Myocardial Infarction/surgery , Myocardium/pathology , Stem Cell Transplantation , Animals , Cell Proliferation , Cell Survival , Cells, Cultured , Contrast Media , Dextrans , Disease Models, Animal , Echocardiography , Feasibility Studies , Female , Ferrosoferric Oxide , Luciferases/genetics , Magnetic Resonance Imaging , Magnetite Nanoparticles , Male , Mice , Mice, Inbred BALB C , Mice, SCID , Myocardial Infarction/pathology , Myocardial Infarction/physiopathology , Recovery of Function , Regeneration , Time Factors , Transfection , Ventricular Function, Left , Ventricular Pressure
15.
Circulation ; 115(10): 1275-84, 2007 Mar 13.
Article in English | MEDLINE | ID: mdl-17339547

ABSTRACT

BACKGROUND: Patients with pulmonary arterial hypertension (PAH) have reduced expression of apolipoprotein E (apoE) and peroxisome proliferator-activated receptor-gamma in lung tissues, and deficiency of both has been linked to insulin resistance. ApoE deficiency leads to enhanced platelet-derived growth factor signaling, which is important in the pathobiology of PAH. We therefore hypothesized that insulin-resistant apoE-deficient (apoE-/-) mice would develop PAH that could be reversed by a peroxisome proliferator-activated receptor-gamma agonist (eg, rosiglitazone). METHODS AND RESULTS: We report that apoE-/- mice on a high-fat diet develop PAH as judged by elevated right ventricular systolic pressure. Compared with females, male apoE-/- were insulin resistant, had lower plasma adiponectin, and had higher right ventricular systolic pressure associated with right ventricular hypertrophy and increased peripheral pulmonary artery muscularization. Because male apoE-/- mice were insulin resistant and had more severe PAH than female apoE-/- mice, we treated them with rosiglitazone for 4 and 10 weeks. This treatment resulted in markedly higher plasma adiponectin, improved insulin sensitivity, and complete regression of PAH, right ventricular hypertrophy, and abnormal pulmonary artery muscularization in male apoE-/- mice. We further show that recombinant apoE and adiponectin suppress platelet-derived growth factor-BB-mediated proliferation of pulmonary artery smooth muscle cells harvested from apoE-/- or C57Bl/6 control mice. CONCLUSIONS: We have shown that insulin resistance, low plasma adiponectin levels, and deficiency of apoE may be risk factors for PAH and that peroxisome proliferator-activated receptor-gamma activation can reverse PAH in an animal model.


Subject(s)
Hypertension, Pulmonary/genetics , Hypertension, Pulmonary/metabolism , Insulin Resistance , PPAR gamma/metabolism , Adiponectin/blood , Adiponectin/pharmacology , Animals , Apolipoproteins E/deficiency , Apolipoproteins E/genetics , Apolipoproteins E/pharmacology , Becaplermin , Cell Proliferation/drug effects , Cells, Cultured , Diet , Disease Models, Animal , Female , Hypertension, Pulmonary/drug therapy , Hypertrophy, Left Ventricular/drug therapy , Hypertrophy, Left Ventricular/genetics , Hypertrophy, Left Ventricular/physiopathology , Hypoglycemic Agents/pharmacology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Muscle, Smooth, Vascular/cytology , Muscle, Smooth, Vascular/drug effects , PPAR gamma/drug effects , Platelet-Derived Growth Factor/antagonists & inhibitors , Platelet-Derived Growth Factor/pharmacology , Proto-Oncogene Proteins c-sis , Risk Factors , Rosiglitazone , Sex Factors , Thiazolidinediones/pharmacology
16.
Am J Physiol Heart Circ Physiol ; 289(6): H2441-9, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16040722

ABSTRACT

Recent data suggest that beta-adrenergic receptor subtypes couple differentially to signaling pathways regulating cardiac function vs. cardiac remodeling. To dissect the roles of beta1- vs. beta2-receptors in the pathogenesis of cardiomyopathy, doxorubicin was administered to beta1, beta2, and beta1/beta2 knockout (-/-) and wild-type mice. Expression and activation of MAPKs were measured. Wild-type and beta1-/- mice showed no acute cardiovascular effects, whereas beta2-/- mice all died within 30 min. The additional deletion of the beta1-receptor (beta1/beta2-/-) totally rescued this toxicity. beta2-/- mice developed decreased contractile function, hypotension, QTc prolongation, and ST segment changes and a 20-fold increase in p38 MAPK activity not seen in the other genotypes. The MAPK inhibitor SB-203580 rescued beta2-/- mice from this acute toxicity. The enhanced toxicity in beta2-/- mice was also recapitulated in wild-type mice with the beta2-selective antagonist ICI-118,551, although the rescue effect of the beta1-deletion was not recapitulated using the beta1-selective antagonist metoprolol or the nonselective beta-antagonist propranolol. These data suggest that beta2-adrenergic receptors play a cardioprotective role in the pathogenesis of cardiomyopathy, whereas beta1-adrenergic receptors mediate at least some of the acute cardiotoxicity of anthracyclines. Differential activation of MAPK isoforms, previously shown in vitro to regulate beta-agonist as well as doxorubicin cardiotoxicity, appears to play a role in mediating the differential effects of these beta-adrenergic receptor subtypes in vivo.


Subject(s)
Blood Pressure , Cardiomyopathy, Dilated/physiopathology , Heart Rate , Receptors, Adrenergic, beta-1/metabolism , Receptors, Adrenergic, beta-2/metabolism , Animals , Cardiotonic Agents , Mice , Mice, Knockout , Survival Rate
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