RhoA protects the mouse heart against ischemia/reperfusion injury

Sunny Yang Xiang, Davy Vanhoutte, Dominic P. Del Re, Nicole H. Purcell, Haiyun Ling, Indroneal Banerjee, Julie B C Bossuyt, Richard A. Lang, Yi Zheng, Scot J. Matkovich, Shigeki Miyamoto, Jeffery D. Molkentin, Gerald W. Dorn, Joan Heller Brown

Research output: Contribution to journalArticle

66 Scopus citations

Abstract

The small GTPase RhoA serves as a nodal point for signaling through hormones and mechanical stretch. However, the role of RhoA signaling in cardiac pathophysiology is poorly understood. To address this issue, we generated mice with cardiomyocyte-specific conditional expression of low levels of activated RhoA (CA-RhoA mice) and demonstrated that they exhibited no overt cardiomyopathy. When challenged by in vivo or ex vivo ischemia/reperfusion (I/R), however, the CA-RhoA mice exhibited strikingly increased tolerance to injury, which was manifest as reduced myocardial lactate dehydrogenase (LDH) release and infarct size and improved contractile function. PKD was robustly activated in CA-RhoA hearts. The cardioprotection afforded by RhoA was reversed by PKD inhibition. The hypothesis that activated RhoA and PKD serve protective physiological functions during I/R was supported by several lines of evidence. In WT mice, both RhoA and PKD were rapidly activated during I/R, and blocking PKD augmented I/R injury. In addition, cardiac-specific RhoA-knockout mice showed reduced PKD activation after I/R and strikingly decreased tolerance to I/R injury, as shown by increased infarct size and LDH release. Collectively, our findings provide strong support for the concept that RhoA signaling in adult cardiomyocytes promotes survival. They also reveal unexpected roles for PKD as a downstream mediator of RhoA and in cardioprotection against I/R.

Original languageEnglish (US)
Pages (from-to)3269-3276
Number of pages8
JournalJournal of Clinical Investigation
Volume121
Issue number8
DOIs
StatePublished - Aug 1 2011

ASJC Scopus subject areas

  • Medicine(all)

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    Xiang, S. Y., Vanhoutte, D., Del Re, D. P., Purcell, N. H., Ling, H., Banerjee, I., Bossuyt, J. B. C., Lang, R. A., Zheng, Y., Matkovich, S. J., Miyamoto, S., Molkentin, J. D., Dorn, G. W., & Brown, J. H. (2011). RhoA protects the mouse heart against ischemia/reperfusion injury. Journal of Clinical Investigation, 121(8), 3269-3276. https://doi.org/10.1172/JCI44371