dilated cardiomyopathy with increased sr ca2+ loading preceded by a hypercontractile state and diastolic failure in the α1ctg mouse扩张型心肌病与sr ca2 +加载之前hypercontractile状态和舒张期失败α1ctg鼠标.pdfVIP

Dilated Cardiomyopathy with Increased SR Ca2+ Loading Preceded by a Hypercontractile State and Diastolic Failure in the a1CTG Mouse 1. 1. 2. 2 1¤ 2 Su Wang , Bruce Ziman , Ilona Bodi , Marta Rubio , Ying-Ying Zhou , Karen D’Souza , Nanette H. 3 2 1 Bishopric , Arnold Schwartz *, Edward G. Lakatta * 1 Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland, United States of America, 2 Institute of Molecular Pharmacology and Biophysics, Department of Surgery, University of Cincinnati, College of Medicine, Cincinnati, Ohio, United States of America, 3 Department of Molecular and Cellular Pharmacology, Medicine and Pediatrics, University of Miami Miller School of Medicine, Miami, Florida, United States of America Abstract Mice over-expressing the a12subunit (pore) of the L-type Ca2+ channel (a1CTG) by 4months (mo) of age exhibit an enlarged heart, hypertrophied myocytes, increased Ca2+ current and Ca2+ transient amplitude, but a normal SR Ca2+ load. With advancing age (8–11 mo), some mice demonstrate advanced hypertrophy but are not in congestive heart failure (NFTG), while others evolve to frank dilated congestive heart failure (FTG). We demonstrate that older NFTG myocytes exhibit a hypercontractile state over a wide range of stimulation frequencies, but maintain a normal SR Ca2+ load compared to age matched non-transgenic (NTG) myocytes. However, at high stimulation rates (2–4 Hz) signs of diastolic contractile failure appear in NFTG cells. The evolution of frank congestive failure in FTG is accompanied by a further increase in heart mass and myocyte