Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An important event in the pathogenesis of heart failure is the development of pathological cardiac hypertrophy. In cultured cardiomyocytes, the transcription factor Gata4 is required for agonist-induced hypertrophy. We hypothesized that, in the intact organism, Gata4 is an important regulator of postnatal heart function and of the hypertrophic response of the heart to pathological stress. To test this hypothesis, we studied mice heterozygous for deletion of the second exon of Gata4 (G4D). At baseline, G4D mice had mild systolic and diastolic dysfunction associated with reduced heart weight and decreased cardiomyocyte number. After transverse aortic constriction (TAC), G4D mice developed overt heart failure and eccentric cardiac hypertrophy, associated with significantly increased fibrosis and cardiomyocyte apoptosis. Inhibition of apoptosis by overexpression of the insulin-like growth factor 1 receptor prevented TAC-induced heart failure in G4D mice. Unlike WT-TAC controls, G4D-TAC cardiomyocytes hypertrophied by increasing in length more than width. Gene expression profiling revealed up-regulation of genes associated with apoptosis and fibrosis, including members of the TGF-beta pathway. Our data demonstrate that Gata4 is essential for cardiac function in the postnatal heart. After pressure overload, Gata4 regulates the pattern of cardiomyocyte hypertrophy and protects the heart from load-induced failure.
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PMID:Gata4 is required for maintenance of postnatal cardiac function and protection from pressure overload-induced heart failure. 1698 87

Transforming growth factor (TGF-beta) is a multifunctional peptide growth factor that has an important role in the regulation of cell growth, differentiation, and repair in a variety of tissues. In mammals, the cytokine has three isoforms, TGF-beta1, TGF-beta2, and TGF-beta3. TGF- beta1 is up-regulated by Ang II and induction of TGF-beta1 causes cardiac fibrosis. The stimulus that triggers the expression of TGF-beta1 may be repeated causing continual injury, which is associated with an increase in the activity of Ang II in heart tissue. The interplay between Ang II and TGF-beta1 causes continued activation that may result in chronic hypertension and progressive myocardial fibrosis, leading to heart failure. The regulation of TGF-beta1 secretion and action involves complex transcriptional events. Overproduction of TGF-beta1 underlies tissue fibrosis. Understanding the actions and signaling transduction of TGF-beta could lead to the development of therapeutic options that may be effective in inhibiting myocardial fibrosis triggered by TGF-beta1 in heart failure.
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PMID:Role of transforming growth factor-beta in the progression of heart failure. 1701 66

A shift in energy substrate utilization from fatty acids to glucose has been reported in failing hearts, resulting in improved oxygen efficiency yet perhaps also contributing to a state of energy deficiency. Peroxisome proliferator-activated receptor (PPAR)-alpha, the principal transcriptional regulator of cardiac fatty acid beta-oxidation (FAO) genes, is downregulated in heart failure, and this may contribute to reduced fatty acid utilization. Cardiomyopathic states are also accompanied by elevated levels of circulating cytokines, such as tumor necrosis factor (TNF), as well as increased local production of cytokines and profibrotic factors, such as transforming growth factor (TGF)-beta. However, whether these molecular pathways directly modulate cardiac energy metabolism and PPAR-alpha activity is not known. Therefore, FAO capacity and FAO gene expression were determined in mice with cardiac-restricted overexpression of TNF (MHCsTNF(3)). MHCsTNF(3) hearts had significantly lower FAO capacity and decreased expression of PPAR-alpha and FAO target genes compared with control hearts. Surprisingly, TNF had little effect on PPAR-alpha activity and FAO rates in cultured ventricular myocytes, suggesting that TNF acts indirectly on myocyte FAO in vivo. We found that TGF-beta expression was upregulated in MHCsTNF(3) hearts and that treatment of cultured myocytes with TGF-beta significantly suppressed FAO rates and directly impaired PPAR-alpha activity, a result reproduced by Smad3 overexpression. This work demonstrates that TGF-beta signaling pathways directly suppress PPAR-alpha activity and reduce FAO in cardiac myocytes, perhaps in response to locally elevated TNF. Although speculative, TGF-beta-driven repair mechanisms may also include the additional benefit of limiting FAO in injured myocardium.
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PMID:Inhibition of PPAR-alpha activity in mice with cardiac-restricted expression of tumor necrosis factor: potential role of TGF-beta/Smad3. 1709 24

Clinical myocarditis is a precursor to dilated cardiomyopathy and a principal cause of heart failure. Nearly 30% of all recently diagnosed cases of myocarditis are attributable to infection with coxsackie B virus (CBV), the most frequently associated pathogen. CBV initially replicates in the pancreas and quickly spreads to the heart, inducing chronic autoimmunity. To determine whether immunosuppressive cytokines could act to limit the extent of autoimmunity to the heart, we infected transgenic mice that express immunosuppressive cytokines in the pancreas. Herein, we demonstrate that transgenic expression of transforming growth factor-beta (1) (TGF-beta) within the pancreatic beta cells prevented mice from developing autoimmune myocarditis after CBV infection. In contrast, transgenic expression of interleukin-4 did not inhibit virus-mediated heart disease. Furthermore, we show that TGF-beta expression reduced viral replication while promoting the recruitment of macrophages into the pancreas. These results illustrate the benefit of TGF-beta in controlling not only viral replication, but also CBV-mediated autoimmunity.
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PMID:Transforming growth factor-beta inhibits coxsackievirus-mediated autoimmune myocarditis. 1720 67

We investigated the effect of the angiotensin type 1 (AT-1) receptor antagonist, irbesartan, on matrix metalloproteinase (MMP) activity and cardiac cytokines in an animal model of diabetic cardiomyopathy. Diabetes was induced in 20 C57/bl6 mice by injection of streptozotocin (STZ). These animals were treated with irbesartan or placebo and were compared with nondiabetic controls. Left ventricular (LV) function was measured by pressure-volume loops with parameters for systolic function (end systolic elastance [Ees]) and diastolic function (cardiac stiffness) 8 weeks after STZ treatment. The cardiac protein content of interleukin (IL)1beta and transforming growth factor (TGF)beta1 were measured by enzyme-linked immunosorbent assay. The total cardiac collagen content and collagen type 1 and 3 were measured by histochemistry, and MMP-2 activity was measured by gelatin zymography. LV dysfunction was documented by impaired Ees and diastolic stiffness in STZ mice compared with controls. This was accompanied by increased TGFbeta, IL1beta, and fibrosis and decreased MMP-2 activity. Treatment with irbesartan attenuated LV dysfunction, IL1beta, TGFbeta, and cardiac fibrosis compared with untreated diabetic animals and normalized MMP activity. These findings present evidence that AT-1 receptor antagonists attenuate cardiac failure by decreasing cardiac inflammation and normalizing MMP activity, leading to normalized cardiac fibrosis in STZ-induced diabetic cardiomyopathy.
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PMID:Contributions of inflammation and cardiac matrix metalloproteinase activity to cardiac failure in diabetic cardiomyopathy: the role of angiotensin type 1 receptor antagonism. 1732 31

Transforming growth factor-beta(1) (TGF-beta(1)) signal and downstream Smads play an important role in tissue fibrosis and matrix remodeling in various etiologies of heart failure. Inhibitory Smad7 (I-Smad7) is an inducible regulatory Smad protein that antagonizes TGF-beta(1) signal mediated via direct abrogation of R-Smad phosphorylation. The effect of ectopic I-Smad7 on net collagen production was investigated using hydroxyproline assay. Adenovirus-mediated I-Smad7 gene (at 100 multiplicity of infection) transfer was associated with significant decrease of collagen synthesis in the presence and absence of TGF-beta(1) in primary rat cardiac myofibroblasts. In I-Smad7-infected cells, we also observed the ablation of TGF-beta(1)-induced R-Smad2 phosphorylation vs. LacZ controls. Overdriven I-Smad7 was associated with significantly increased expression of immunoreactive 65-kDa matrix metalloproteinase-2 (MMP-2) protein in culture medium of myofibroblast compared with LacZ-infected cells. Expression of the 72-kDa MMP-2 variant, e.g., the inactive form, was not altered by exogenous I-Smad7 transfection/overexpression. Furthermore, I-Smad7 overexpression was associated with a significant increase and decrease in expression of p27 and phospho-Rb protein, respectively, as well as reduced [(3)H]thymidine incorporation vs. Ad-LacZ-infected controls. We suggest that negative modulation of R-Smad phosphorylation by ectopic I-Smad7 may contribute to the downregulation of collagen in cardiac myofibroblasts and may suppress the proliferation of these cells. Thus treatments targeting the collagen deposition by overexpression of I-Smad7 may provide a new therapeutic strategy for cardiac fibrosis.
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PMID:Regulation of collagen synthesis by inhibitory Smad7 in cardiac myofibroblasts. 1751 91

Cardiac remodelling is a key risk factor for the development of heart failure in the chronic phase following myocardial infarction. Our previous studies have shown an anti-remodelling role of ACE2 (angiotensin-converting enzyme 2) in vivo during hypertension and that these protective effects are mediated through increased circulating levels of Ang-(1-7) [angiotensin-(1-7)]. In the present study, we have demonstrated that cardiac myocytes have modest ACE2 activity, whereas cardiac fibroblasts do not exhibit any endogenous activity. As fibroblasts are the major cell type found in an infarct zone following a myocardial infarction, we examined the effects of ACE2 gene delivery to cultured cardiac fibroblasts after acute hypoxic exposure. Cardiac fibroblasts from 5-day-old Sprague-Dawley rat hearts were grown to confluence and transduced with a lentiviral vector containing murine ACE2 cDNA under transcriptional control by the EF1alpha (elongation factor 1alpha) promoter (lenti-ACE2). Transduction of fibroblasts with lenti-ACE2 resulted in a viral dose-dependent increase in ACE2 activity. This was associated with a significant attenuation of both basal and hypoxia/re-oxygenation-induced collagen production by the fibroblasts. Cytokine production, specifically TGFbeta (transforming growth factor beta), by these cells was also significantly attenuated by ACE2 expression. Collectively, these results indicate that: (i) endogenous ACE2 activity is observed in cardiac myocytes, but not in cardiac fibroblasts; (ii) ACE2 overexpression in the cardiac fibroblast attenuates collagen production; and (iii) this prevention is probably mediated by decreased expression of cytokines. We conclude that ACE2 expression, limited to cardiac fibroblasts, may represent a novel paradigm for in vivo therapy following acute ischaemia.
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PMID:ACE2 overexpression inhibits hypoxia-induced collagen production by cardiac fibroblasts. 1760 May 30

Epsilon protein kinase C (epsilonPKC) plays pivotal roles in myocardial infarction and in heart failure. Although cardiac transplantation is a well-established therapy for severe heart failure, allograft rejection and host inflammatory responses limit graft function and reduce life expectancy. Here we determined whether sustained epsilonPKC inhibition beginning 3 days after transplantation suppress allograft rejection and improve cardiac transplantation using a murine heterotopic transplantation model. Hearts of FVB mice (H-2(q)) were transplanted into C57BL/6 mice (H-2(b)). Delivery of the epsilonPKC inhibitor, TAT(47-57)-epsilonV1-2 (epsilonV1-2, n=9, 20 mg/kg/day), or the carrier control peptide, TAT(47-57) (TAT, n=8), by osmotic pump began 3 days after transplantation and continued for the remaining 4 weeks. epsilonV1-2 treatment significantly improved the beating score throughout the treatment. Infiltration of macrophages and T cells into the cardiac grafts was significantly reduced and parenchymal fibrosis was decreased in animals treated with epsilonV1-2 as compared with control treatment. Finally, the rise in pro-fibrotic cytokine, TGF-beta and monocyte recruiting chemokine MCP-1 levels was almost abolished by epsilonV1-2 treatment, whereas the rise in PDGF-BB level was unaffected. These data suggest that epsilonPKC activity contributes to the chronic immune response in cardiac allograft and that an epsilonPKC-selective inhibitor, such as epsilonV1-2, could augment current therapeutic strategies to suppress inflammation and prolong graft survival in humans.
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PMID:Pharmacological inhibition of epsilon PKC suppresses chronic inflammation in murine cardiac transplantation model. 1770 96

Atrial fibrillation (AF) is the most commonly occurring arrhythmia in clinical practice, however, the mechanism of atrial fibrillation is not well explained. It has been considered that myocardial fibrosis plays a role in atrial fibrillation. Within the heart, this fibrosis is thought to be mediated by transforming growth factor-beta 1 (TGF-beta 1), a potent stimulator of collagen-producing cardiac fibroblasts. Recent studies indicate that atrial fibrillation is associated with elevated serum concentrations of TGF-beta 1 and C-terminal propeptide of procollagen type I (a marker of collagen type I synthesis). TGF-beta 1 was not only associated with the presence of atrial fibrillation but may also predict patients at increased risk for future development of atrial fibrillation. Why TGF-beta 1 in atrial fibrillation is high is a puzzling problem. We hypothesized that TGF-beta 1 is a possible cause of atrial fibrillation by initiating fibrosis response. Atrial interstitial fibrosis has been seen in patients with CHF and in animal models of pacing-induced heart failure. It was demonstrated that TGF-beta 1 levels were increased in the atria after the development of congestive heart failure in dogs. In a similar study, mice with increased expression of TGF-beta 1 were prone to atrial fibrillation development as a result of raised levels of atrial fibrosis. If the hypothesis is confirmed, administration of TGF-beta 1 monoclonal antibodies may be used to eliminate the etiology. It will be a new target point to treat atrial fibrillation.
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PMID:The fibrosis and atrial fibrillation: is the transforming growth factor-beta 1 a candidate etiology of atrial fibrillation. 1832 83

Chromatin remodeling, particularly histone acetylation, plays a critical role in the progression of pathological cardiac hypertrophy and heart failure. We hypothesized that curcumin, a natural polyphenolic compound abundant in the spice turmeric and a known suppressor of histone acetylation, would suppress cardiac hypertrophy through the disruption of p300 histone acetyltransferase-dependent (p300-HAT-dependent) transcriptional activation. We tested this hypothesis using primary cultured rat cardiac myocytes and fibroblasts as well as two well-established mouse models of cardiac hypertrophy. Curcumin blocked phenylephrin-induced (PE-induced) cardiac hypertrophy in vitro in a dose-dependent manner. Furthermore, curcumin both prevented and reversed mouse cardiac hypertrophy induced by aortic banding (AB) and PE infusion, as assessed by heart weight/BW and lung weight/BW ratios, echocardiographic parameters, and gene expression of hypertrophic markers. Further investigation demonstrated that curcumin abrogated histone acetylation, GATA4 acetylation, and DNA-binding activity through blocking p300-HAT activity. Curcumin also blocked AB-induced inflammation and fibrosis through disrupting p300-HAT-dependent signaling pathways. Our results indicate that curcumin has the potential to protect against cardiac hypertrophy, inflammation, and fibrosis through suppression of p300-HAT activity and downstream GATA4, NF-kappaB, and TGF-beta-Smad signaling pathways.
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PMID:Curcumin prevents and reverses murine cardiac hypertrophy. 1960 50


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