Genetics and Disease of Ventricular Muscle

Fatkin, Diane; Seidman, Christine E.

doi:10.1101/cshperspect.a021063

Cited by 42 publications

(42 citation statements)

References 120 publications

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“…However, it remains unknown whether this strategy provides longer-term benefit or is effective when administered in the perireperfusion phase. In addition to studying acquired forms of HF, it will also be of interest to study the role of BET proteins in the pathogenesis of cardiomyopathies driven by genetic mutations (51), some of which feature extensive activation of profibrotic and proinflammatory pathways in the heart. These lines of investigation, guided by the results of ongoing human cancer trials, will provide the critical foundation for developing BET bromodomain inhibition as a potential therapeutic strategy in human heart disease.…”

Section: Discussionmentioning

confidence: 99%

BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure

et al. 2017

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Despite current standard of care, the average 5-year mortality after an initial diagnosis of heart failure (HF) is about 40%, reflecting an urgent need for new therapeutic approaches. Previous studies demonstrated that the epigenetic reader protein bromodomain-containing protein 4 (BRD4), an emerging therapeutic target in cancer, functions as a critical coactivator of pathologic gene transactivation during cardiomyocyte hypertrophy. However, the therapeutic relevance of these findings to human disease remained unknown. We demonstrate that treatment with the BET bromodomain inhibitor JQ1 has therapeutic effects during severe, preestablished HF from prolonged pressure overload, as well as after a massive anterior myocardial infarction in mice. Furthermore, JQ1 potently blocks agonist-induced hypertrophy in human induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs). Integrated transcriptomic analyses across animal models and human iPSC-CMs reveal that BET inhibition preferentially blocks transactivation of a common pathologic gene regulatory program that is robustly enriched for NFκB and TGF-β signaling networks, typified by innate inflammatory and profibrotic myocardial genes. As predicted by these specific transcriptional mechanisms, we found that JQ1 does not suppress physiological cardiac hypertrophy in a mouse swimming model. These findings establish that pharmacologically targeting innate inflammatory and profibrotic myocardial signaling networks at the level of chromatin is effective in animal models and human cardiomyocytes, providing the critical rationale for further development of BET inhibitors and other epigenomic medicines for HF.

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Section: Discussionmentioning

confidence: 99%

BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure

et al. 2017

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“…DCM results from a variety of environmental factors, such as viral infection and alcohol abuse, as well as from mutations in a number of genes including titin, lamin A/C, cardiac actin, cardiac myosin heavy chain, and phospholamban (reviewed in refs. [4][5][6]. Whether all of these DCM-inducing factors activate the same or different cellular pathways to produce similar clinical features remains uncertain.…”

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confidence: 99%

Cardiac myosin binding protein C regulates postnatal myocyte cytokinesis

Jiang

Burgon

Wakimoto

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Homozygous cardiac myosin binding protein C-deficient (Mybpc t/t ) mice develop dramatic cardiac dilation shortly after birth; heart size increases almost twofold. We have investigated the mechanism of cardiac enlargement in these hearts. Throughout embryogenesis myocytes undergo cell division while maintaining the capacity to pump blood by rapidly disassembling and reforming myofibrillar components of the sarcomere throughout cell cycle progression. Shortly after birth, myocyte cell division ceases. Cardiac MYBPC is a thick filament protein that regulates sarcomere organization and rigidity. We demonstrate that many Mybpc t/t myocytes undergo an additional round of cell division within 10 d postbirth compared with their wild-type counterparts, leading to increased numbers of mononuclear myocytes. Short-hairpin RNA knockdown of Mybpc3 mRNA in wild-type mice similarly extended the postnatal window of myocyte proliferation. However, adult Mybpc t/t myocytes are unable to fully regenerate the myocardium after injury. MYBPC has unexpected inhibitory functions during postnatal myocyte cytokinesis and cell cycle progression. We suggest that human patients with homozygous MYBPC3-null mutations develop dilated cardiomyopathy, coupled with myocyte hyperplasia (increased cell number), as observed in Mybpc t/t mice. Human patients, with heterozygous truncating MYBPC3 mutations, like mice with similar mutations, have hypertrophic cardiomyopathy. However, the mechanism leading to hypertrophic cardiomyopathy in heterozygous MYBPC3 +/− individuals is myocyte hypertrophy (increased cell size), whereas the mechanism leading to cardiac dilation in homozygous Mybpc3 −/− mice is primarily myocyte hyperplasia.myosin binding protein C | cardiac dilation | cardiac hypertrophy | cytokinesis | hyperplasia

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“…Over 300 mutations in sarcomere proteins have been shown as causes of DCM and other heart diseases (Morita et al, 2005). Human genetic studies have shown that many familial DCM cases are linked to alterations in sarcomere proteins such as cardiac actin ( ACTC1 ), myosin-binding protein C ( MYBPC3 ), α-myosin heavy chain ( MYH6 ), β-myosin heavy chain ( MYH7 ), troponin C ( TNNC1 ), troponin I ( TNNI3 ), troponin T ( TNNT2 ), α-tropomyosin ( TPM1 ), and titin ( TTN ) (Fatkin et al, 2014; Kamisago et al, 2000). …”

Section: Mutations In Sarcomere Proteins Leading To Dcmmentioning

confidence: 99%

“…Among genes encoding these proteins, mutations in MYH7 and TTN are most common in familial DCM cases (Fatkin et al, 2014; Sanbe, 2013). MYH7 encodes the β-myosin heavy chain (MHC-β), which is predominantly found in the heart and it forms the thick filament in the cardiac muscle together with other regulatory light chain proteins encoded by MYL2 and MYL3 .…”

Section: Mutations In Sarcomere Proteins Leading To Dcmmentioning

confidence: 99%

Genetic Variations Leading to Familial Dilated Cardiomyopathy

Cho

Lee

Kim

2016

Molecules and Cells

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Cardiomyopathy is a major cause of death worldwide. Based on pathohistological abnormalities and clinical manifestation, cardiomyopathies are categorized into several groups: hypertrophic, dilated, restricted, arrhythmogenic right ventricular, and unclassified. Dilated cardiomyopathy, which is characterized by dilation of the left ventricle and systolic dysfunction, is the most severe and prevalent form of cardiomyopathy and usually requires heart transplantation. Its etiology remains unclear. Recent genetic studies of single gene mutations have provided significant insights into the complex processes of cardiac dysfunction. To date, over 40 genes have been demonstrated to contribute to dilated cardiomyopathy. With advances in genetic screening techniques, novel genes associated with this disease are continuously being identified. The respective gene products can be classified into several functional groups such as sarcomere proteins, structural proteins, ion channels, and nuclear envelope proteins. Nuclear envelope proteins are emerging as potential molecular targets in dilated cardiomyopathy. Because they are not directly associated with contractile force generation and transmission, the molecular pathways through which these proteins cause cardiac muscle disorder remain unclear. However, nuclear envelope proteins are involved in many essential cellular processes. Therefore, integrating apparently distinct cellular processes is of great interest in elucidating the etiology of dilated cardiomyopathy. In this mini review, we summarize the genetic factors associated with dilated cardiomyopathy and discuss their cellular functions.

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Genetics and Disease of Ventricular Muscle

Cited by 42 publications

References 120 publications

BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure

BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure

Cardiac myosin binding protein C regulates postnatal myocyte cytokinesis

Genetic Variations Leading to Familial Dilated Cardiomyopathy

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