Abstract |
Heart failure is accompanied by a loss of the orderly disposition of transverse (T)-tubules and a decrease of their associations with the junctional sarcoplasmic reticulum (jSR). Junctophilin-2 (JP2) is a structural protein responsible for jSR/T-tubule docking. Animal models of cardiac stresses demonstrate that down-regulation of JP2 contributes to T-tubule disorganization, loss of excitation-contraction coupling, and heart failure development. Our objective was to determine whether JP2 overexpression attenuates stress-induced T-tubule disorganization and protects against heart failure progression. We therefore generated transgenic mice with cardiac-specific JP2 overexpression (JP2-OE). Baseline cardiac function and Ca(2+) handling properties were similar between JP2-OE and control mice. However, JP2-OE mice displayed a significant increase in the junctional coupling area between T-tubules and the SR and an elevated expression of the Na(+)/Ca(2+) exchanger, although other excitation-contraction coupling protein levels were not significantly changed. Despite similar cardiac function at baseline, overexpression of JP2 provided significantly protective benefits after pressure overload. This was accompanied by a decreased percentage of surviving mice that developed heart failure, as well as preservation of T-tubule network integrity in both the left and right ventricles. Taken together, these data suggest that strategies to maintain JP2 levels can prevent the progression from hypertrophy to heart failure.
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Authors | Ang Guo, Xiaoying Zhang, Venkat Ramesh Iyer, Biyi Chen, Caimei Zhang, William J Kutschke, Robert M Weiss, Clara Franzini-Armstrong, Long-Sheng Song |
Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 111
Issue 33
Pg. 12240-5
(Aug 19 2014)
ISSN: 1091-6490 [Electronic] United States |
PMID | 25092313
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Membrane Proteins
- Muscle Proteins
- junctophilin-2 protein, mouse
- Calcium
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Topics |
- Animals
- Calcium
(metabolism)
- Heart Failure
(metabolism, physiopathology)
- Membrane Proteins
(metabolism)
- Mice
- Mice, Transgenic
- Muscle Proteins
(metabolism)
- Myocytes, Cardiac
(metabolism)
- Stress, Physiological
- Ventricular Pressure
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