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Chopra, Anant

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Chopra

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Anant

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Chopra, Anant

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2015 - 20162

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Author's Publications: search.filters.isAuthorOfPublication.7a779050-d21a-4264-a12a-63363efebbb4

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    Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy
    (American Association for the Advancement of Science (AAAS), 2015) Hinson, John Travis; Chopra, Anant; Nafissi, N.; Polacheck, William J.; Benson, Craig Carlyle; Swist, S.; Gorham, Joshua; Yang, Luhan; Schafer, S.; Sheng, Calvin Chen; Haghighi, Alireza; Homsy, Jason; Hubner, N.; Church, George; Cook, S. A.; Linke, Wolfgang; Chen, Christopher; Seidman, Jonathan; Seidman, Christine
    Human mutations that truncate the massive sarcomere protein titin [TTN-truncating variants (TTNtvs)] are the most common genetic cause for dilated cardiomyopathy (DCM), a major cause of heart failure and premature death. Here we show that cardiac microtissues engineered from human induced pluripotent stem (iPS) cells are a powerful system for evaluating the pathogenicity of titin gene variants. We found that certain missense mutations, like TTNtvs, diminish contractile performance and are pathogenic. By combining functional analyses with RNA sequencing, we explain why truncations in the A-band domain of TTN cause DCM, whereas truncations in the I band are better tolerated. Finally, we demonstrate that mutant titin protein in iPS cell–derived cardiomyocytes results in sarcomere insufficiency, impaired responses to mechanical and β-adrenergic stress, and attenuated growth factor and cell signaling activation. Our findings indicate that titin mutations cause DCM by disrupting critical linkages between sarcomerogenesis and adaptive remodeling.
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    Non-cell autonomous cues for enhanced functionality of human embryonic stem cell-derived cardiomyocytes via maturation of sarcolemmal and mitochondrial KATP channels
    (Nature Publishing Group, 2016) Keung, Wendy; Ren, Lihuan; Sen Li; Wong, Andy On-Tik; Chopra, Anant; Kong, Chi-Wing; Tomaselli, Gordon F.; Chen, Christopher; Li, Ronald A.
    Human embryonic stem cells (hESCs) is a potential unlimited ex vivo source of ventricular (V) cardiomyocytes (CMs), but hESC-VCMs and their engineered tissues display immature traits. In adult VCMs, sarcolemmal (sarc) and mitochondrial (mito) ATP-sensitive potassium (KATP) channels play crucial roles in excitability and cardioprotection. In this study, we aim to investigate the biological roles and use of sarcKATP and mitoKATP in hESC-VCM. We showed that SarcIK, ATP in single hESC-VCMs was dormant under baseline conditions, but became markedly activated by cyanide (CN) or the known opener P1075 with a current density that was ~8-fold smaller than adult; These effects were reversible upon washout or the addition of GLI or HMR1098. Interestingly, sarcIK, ATP displayed a ~3-fold increase after treatment with hypoxia (5% O2). MitoIK, ATP was absent in hESC-VCMs. However, the thyroid hormone T3 up-regulated mitoIK, ATP, conferring diazoxide protective effect on T3-treated hESC-VCMs. When assessed using a multi-cellular engineered 3D ventricular cardiac micro-tissue (hvCMT) system, T3 substantially enhanced the developed tension by 3-folds. Diazoxide also attenuated the decrease in contractility induced by simulated ischemia (1% O2). We conclude that hypoxia and T3 enhance the functionality of hESC-VCMs and their engineered tissues by selectively acting on sarc and mitoIK, ATP.