Abnormal Calcium Handling Properties Underlie Familial Hypertrophic Cardiomyopathy Pathology in Patient-Specific Induced Pluripotent Stem Cells

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• 作者：Feng Lan¹ ; ² ; ³ ; ¹² ; Andrew S. Lee¹ ; ² ; ³ ; ¹² ; Ping Liang¹ ; ² ; ³ ; ¹² ; Veronica Sanchez-Freire¹ ; ² ; ³ ; Patricia K. Nguyen¹ ; Li Wang¹ ; ² ; Leng Han¹ ; ² ; Michelle Yen⁴ ; Yongming Wang¹ ; ² ; ³ ; Ning Sun¹ ; ² ; Oscar J. Abilez⁵ ; Shijun Hu¹ ; ² ; ³ ; Antje D. Ebert¹ ; ² ; ³ ; Enrique G. Navarrete² ; Chelsey S. Simmons⁹ ; Matthew Wheeler¹ ; Beth Pruitt⁹ ; Richard Lewis⁴ ; Yoshinori Yamaguchi¹⁰ ; Euan A. Ashley¹ ; Donald M. Bers¹¹ ; Robert C. Robbins² ; ⁶ ; Michael T. Longaker³ ; ⁸ ; Joseph C. Wu¹ ; ² ; ³ ; ⁷ ; ^{joewu@stanford.edu}
• 刊名：Cell Stem Cell
• 出版年：2013
• 出版时间：3 January, 2013
• 年：2013
• 卷：12
• 期：1
• 页码：101-113
• 全文大小：2268 K

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Summary

Familial hypertrophic cardiomyopathy (HCM) is?a prevalent hereditary cardiac disorder linked to arrhythmia and sudden cardiac death. While the causes of HCM have been identified as genetic mutations in the cardiac sarcomere, the pathways by which sarcomeric mutations engender myocyte hypertrophy and electrophysiological abnormalities are not understood. To elucidate the mechanisms underlying HCM development, we generated patient-specific induced pluripotent stem cell cardiomyocytes (iPSC-CMs) from a ten-member family cohort carrying a hereditary HCM missense mutation (Arg663His) in the MYH7 gene. Diseased iPSC-CMs recapitulated numerous aspects of the HCM phenotype including cellular enlargement and contractile arrhythmia at the single-cell level. Calcium (Ca²⁺) imaging indicated dysregulation of Ca²⁺ cycling and elevation in intracellular Ca²⁺ ([Ca²⁺]_i) are central mechanisms for disease pathogenesis. Pharmacological restoration of Ca²⁺ homeostasis prevented development of hypertrophy and electrophysiological irregularities. We anticipate that these findings will help elucidate the mechanisms underlying HCM development and identify novel therapies for the disease.