Apoptosis and heart failure: clinical relevance and therapeutic target

Garg, Shuchita; Narula, Jagat; Chandrashekhar, Y.

doi:10.1016/j.yjmcc.2004.11.006

Cited by 90 publications

(53 citation statements)

References 72 publications

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“…Loss of cardiomyocytes through cell death regardless of the underlying cause has been implied in the pathogenesis of cardiomyopathies. 30 Elegant proof has been provided in transgenic mice expressing low levels of active caspase-8 and Mst-1 in the heart. 31,32 In both models, a gradual loss of cardiomyocytes resulting from apoptosis has been implied to be the cause of heart failure and death.…”

Section: Levkau Et Almentioning

confidence: 99%

Survivin Determines Cardiac Function by Controlling Total Cardiomyocyte Number

et al. 2008

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Background-Survivin inhibits apoptosis and regulates cell division in many organs, but its function in the heart is unknown. Methods and Results-We show that cardiac-specific deletion of survivin resulted in premature cardiac death. The underlying cause was a dramatic reduction in total cardiomyocyte numbers as determined by a stereological method for quantification of cells per organ. The resulting increased hemodynamic load per cell led to progressive heart failure as assessed by echocardiography, magnetic resonance imaging, positron emission tomography, and invasive catheterization. The reduction in total cardiomyocyte number in ␣-myosin heavy chain (MHC)-survivin Ϫ/Ϫ mice was due to an Ϸ50% lower mitotic rate without increased apoptosis. This occurred at the expense of DNA accumulation because survivin-deficient cardiomyocytes displayed marked DNA polyploidy indicative of consecutive rounds of DNA replication without cell division. Survivin small interfering RNA knockdown in neonatal rat cardiomyocytes also led to polyploidization and cell cycle arrest without apoptosis. Adenoviral overexpression of survivin in cardiomyocytes inhibited doxorubicin-induced apoptosis, induced DNA synthesis, and promoted cell cycle progression. The phenotype of the ␣MHC-survivin Ϫ/Ϫ mice also allowed us to determine the minimum cardiomyocyte number sufficient for normal cardiac function. In human cardiomyopathy, survivin was potently induced in the failing heart and downregulated again after hemodynamic support by a left ventricular assist device. Its expression positively correlated with the mean cardiomyocyte DNA content. Conclusions-We suggest that the ontogenetically determined cardiomyocyte number may be an independent factor in the susceptibility to cardiac diseases. Through its profound impact on both cardiomyocyte replication and apoptosis, survivin may emerge as a promising new target for myocardial regeneration.

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Section: Levkau Et Almentioning

confidence: 99%

Survivin Determines Cardiac Function by Controlling Total Cardiomyocyte Number

et al. 2008

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“…The present study demonstrated that baicalin attenuates cardiac fibrosis induced by pressure overload in vivo , as indicated by decreased extracellular matrix and lower expression of fibrogenic genes (Collagen I, Collagen III and CTGF). Additionally, apoptosis contributes to heart failure by decreasing the number of myocardial cells [33]. Even very low, but persistent, levels of apoptosis of myocardial cells gradually resulted in left ventricular dilation, systolic and diastolic dysfunction, and lethal dilated cardiomyopathy [26].…”

Section: Discussionmentioning

confidence: 99%

Baicalin Attenuates Cardiac Dysfunction and Myocardial Remodeling in a Chronic Pressure-Overload Mice Model

Zhang

Liao

Zhu

et al. 2017

Cell Physiol Biochem

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Background/Aims: Baicalin has been shown to be effective for various animal models of cardiovascular diseases, such as pulmonary hypertension, atherosclerosis and myocardial ischaemic injury. However, whether baicalin plays a role in cardiac hypertrophy remains unknown. Here we investigated the protective effects of baicalin on cardiac hypertrophy induced by pressure overload and explored the potential mechanisms involved. Methods: C57BL/6J-mice were treated with baicalin or vehicle following transverse aortic constriction or Sham surgery for up to 8 weeks, and at different time points, cardiac function and heart size measurement and histological and biochemical examination were performed. Results: Mice under pressure overload exhibited cardiac dysfunction, high mortality, myocardial hypertrophy, increased apoptosis and fibrosis markers, and suppressed cardiac expression of PPARα and PPARβ/δ. However, oral administration of baicalin improved cardiac dysfunction, decreased mortality, and attenuated histological and biochemical changes described above. These protective effects of baicalin were associated with reduced heart and cardiomyocyte size, lower fetal genes expression, attenuated cardiac fibrosis, lower expression of profibrotic markers, and decreased apoptosis signals in heart tissue. Moreover, we found that baicalin induced PPARα and PPARβ/δ expression in vivo and in vitro. Subsequent experiments demonstrated that long-term baicalin treatment presented no obvious cardiac lipotoxicity. Conclusions: The present results demonstrated that baicalin attenuates pressure overload induced cardiac dysfunction and ventricular remodeling, which would be due to suppressed cardiac hypertrophy, fibrosis, apoptosis and metabolic abnormality.

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“…A failure in the regulation of apoptosis is associated with autoimmune and degenerative diseases (too much apoptosis) and cancer (too little apoptosis). An increased understanding of the molecular mechanisms of the apoptotic process is expected to provide new insights into disease processes as diverse as cardiac arrest and cancer [1][2][3].…”

Section: Introductionmentioning

confidence: 99%

“…Loss of cardiac mass, due to cardiomyocyte-death, is critical to heart disease progression. Cardiomyocte death has been attributed, in part, to apoptosis and this apoptosis occurs both at the infarct site and in areas of the myocardium distal to the infarct zone [1,2]. Continued apoptosis is observed even after blood flow has been restored to the affected area.…”

Section: Introductionmentioning

confidence: 99%

Identification of an inhibitor of caspase activation from heart extracts; ATP blocks apoptosome formation

et al. 2007

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By revealing the biochemistry of apoptosis it is expected we will both improve our understanding of diseases where apoptosis plays an important role and aid the development of therapies for these disorders. Caspases are a family of proteases whose activity is required for apoptosis. In this study, a cell-free system was used to investigate the mechanism of caspase-9 activation in extracts from heart cells. Unlike extracts from other cell types, heart extracts were found to activate caspases poorly. This could be explained by the low levels of Apaf-1 in heart cells. However, subsequent testing showed that heart extracts contained an inhibitor of caspase activation that could block caspase activation in extracts from different cell types. Subsequent purification of the inhibitor of caspase activation from these extracts identified ATP. Caspase-9 is activated by recruitment into a multi-protein complex, the apoptosome, which then activates downstream caspases that kill the cell. Importantly, size exclusion chromatography showed that ATP inhibits apoptosome formation at physiologically relevant concentrations. Together these data support the hypothesis that intracellular ATP concentration is a critical factor in determining whether an apoptotic stimulus can induce apoptosome formation. Thus, the well described fall in intracellular ATP apoptosis is not an epiphenomenon but may be a pro-apoptotic event contributing to cell death.

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Apoptosis and heart failure: clinical relevance and therapeutic target

Cited by 90 publications

References 72 publications

Survivin Determines Cardiac Function by Controlling Total Cardiomyocyte Number

Survivin Determines Cardiac Function by Controlling Total Cardiomyocyte Number

Baicalin Attenuates Cardiac Dysfunction and Myocardial Remodeling in a Chronic Pressure-Overload Mice Model

Identification of an inhibitor of caspase activation from heart extracts; ATP blocks apoptosome formation

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