Cardiac contractile dysfunction and protein kinase C-mediated myofilament phosphorylation in disease and aging

被引:6
|
作者
Ravichandran, Vani S. [1 ,2 ]
Patel, Himanshu J. [2 ]
Pagani, Francis D. [2 ]
Westfall, Margaret, V [1 ,2 ]
机构
[1] Univ Michigan, Program Cellular & Mol Biol, Ann Arbor, MI 48109 USA
[2] Univ Michigan, Dept Cardiac Surg, Ann Arbor, MI 48109 USA
来源
JOURNAL OF GENERAL PHYSIOLOGY | 2019年 / 151卷 / 09期
基金
美国国家卫生研究院;
关键词
ASSIST DEVICE SUPPORT; TROPONIN-I; HEART-FAILURE; CALCIUM TRANSIENTS; MODULATION; INHIBITION; RECOVERY; EXPRESSION; DEPHOSPHORYLATION; IMPLANTATION;
D O I
10.1085/jgp.201912353
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
Increases in protein kinase C (PKC) are associated with diminished cardiac function, but the contribution of downstream myofilament phosphorylation is debated in human and animal models of heart failure. The current experiments evaluated PKC isoform expression, downstream cardiac troponin I (cTnI) S44 phosphorylation (p-S44), and contractile function in failing (F) human myocardium, and in rat models of cardiac dysfunction caused by pressure overload and aging. In F human myocardium, elevated PKC alpha expression and cTnI p-S44 developed before ventricular assist device implantation. Circulatory support partially reduced PKC alpha expression and cTnI p-544 levels and improved cellular contractile function. Gene transfer of dominant negative PKC alpha (PKC alpha DN) into F human myocytes also improved contractile function and reduced cTnI p-S44. Heightened cTnI phosphorylation of the analogous residue accompanied reduced myocyte contractile function in a rat model of pressure overload and in aged Fischer 344 x Brown Norway F1 rats (>= 26 mo). Together, these results indicate PKC-targeted cTnI p-S44 accompanies cardiac cellular dysfunction in human and animal models. Interfering with PKCa activity reduces downstream cTnI p-S44 levels and partially restores function, suggesting cTnI p-S44 may be a useful target to improve contractile function in the future.
引用
收藏
页码:1070 / 1080
页数:11
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