| Literature DB >> 30409805 |
Ang Guo1, Yihui Wang1,2, Biyi Chen1, Yunhao Wang1, Jinxiang Yuan1, Liyang Zhang3, Duane Hall1, Jennifer Wu1, Yun Shi1, Qi Zhu1,4, Cheng Chen1,2, William H Thiel1, Xin Zhan1, Robert M Weiss1, Fenghuang Zhan1, Catherine A Musselman3, Miles Pufall3, Weizhong Zhu4, Kin Fai Au1, Jiang Hong2, Mark E Anderson5, Chad E Grueter1,6, Long-Sheng Song7,6,8.
Abstract
Junctophilin-2 (JP2) is a structural protein required for normal excitation-contraction (E-C) coupling. After cardiac stress, JP2 is cleaved by the calcium ion-dependent protease calpain, which disrupts the E-C coupling ultrastructural machinery and drives heart failure progression. We found that stress-induced proteolysis of JP2 liberates an N-terminal fragment (JP2NT) that translocates to the nucleus, binds to genomic DNA, and controls expression of a spectrum of genes in cardiomyocytes. Transgenic overexpression of JP2NT in mice modifies the transcriptional profile, resulting in attenuated pathological remodeling in response to cardiac stress. Conversely, loss of nuclear JP2NT function accelerates stress-induced development of hypertrophy and heart failure in mutant mice. These data reveal a self-protective mechanism in failing cardiomyocytes that transduce mechanical information (E-C uncoupling) into salutary transcriptional reprogramming in the stressed heart.Entities:
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Year: 2018 PMID： 30409805 PMCID： PMC6336677 DOI： 10.1126/science.aan3303
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728