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 Citations (Scopus)

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

Fingerprint

Reperfusion Injury
Reperfusion
Ischemia
L-Lactate Dehydrogenase
Cardiac Myocytes
Monomeric GTP-Binding Proteins
Cardiomyopathies
Knockout Mice
Hormones
Wounds and Injuries

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Xiang, S. Y., Vanhoutte, D., Del Re, D. P., Purcell, N. H., Ling, H., Banerjee, I., ... 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

RhoA protects the mouse heart against ischemia/reperfusion injury. / Xiang, Sunny Yang; Vanhoutte, Davy; Del Re, Dominic P.; Purcell, Nicole H.; Ling, Haiyun; Banerjee, Indroneal; Bossuyt, Julie B C; Lang, Richard A.; Zheng, Yi; Matkovich, Scot J.; Miyamoto, Shigeki; Molkentin, Jeffery D.; Dorn, Gerald W.; Brown, Joan Heller.

In: Journal of Clinical Investigation, Vol. 121, No. 8, 01.08.2011, p. 3269-3276.

Research output: Contribution to journalArticle

Xiang, SY, Vanhoutte, D, Del Re, DP, Purcell, NH, Ling, H, Banerjee, I, Bossuyt, JBC, Lang, RA, Zheng, Y, Matkovich, SJ, Miyamoto, S, Molkentin, JD, Dorn, GW & Brown, JH 2011, 'RhoA protects the mouse heart against ischemia/reperfusion injury', Journal of Clinical Investigation, vol. 121, no. 8, pp. 3269-3276. https://doi.org/10.1172/JCI44371
Xiang SY, Vanhoutte D, Del Re DP, Purcell NH, Ling H, Banerjee I et al. RhoA protects the mouse heart against ischemia/reperfusion injury. Journal of Clinical Investigation. 2011 Aug 1;121(8):3269-3276. https://doi.org/10.1172/JCI44371
Xiang, Sunny Yang ; Vanhoutte, Davy ; Del Re, Dominic P. ; Purcell, Nicole H. ; Ling, Haiyun ; Banerjee, Indroneal ; Bossuyt, Julie B C ; Lang, Richard A. ; Zheng, Yi ; Matkovich, Scot J. ; Miyamoto, Shigeki ; Molkentin, Jeffery D. ; Dorn, Gerald W. ; Brown, Joan Heller. / RhoA protects the mouse heart against ischemia/reperfusion injury. In: Journal of Clinical Investigation. 2011 ; Vol. 121, No. 8. pp. 3269-3276.
@article{eb260ec48f3e40d2abc4bd5fee8ba2ef,
title = "RhoA protects the mouse heart against ischemia/reperfusion injury",
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.",
author = "Xiang, {Sunny Yang} and Davy Vanhoutte and {Del Re}, {Dominic P.} and Purcell, {Nicole H.} and Haiyun Ling and Indroneal Banerjee and Bossuyt, {Julie B C} and Lang, {Richard A.} and Yi Zheng and Matkovich, {Scot J.} and Shigeki Miyamoto and Molkentin, {Jeffery D.} and Dorn, {Gerald W.} and Brown, {Joan Heller}",
year = "2011",
month = "8",
day = "1",
doi = "10.1172/JCI44371",
language = "English (US)",
volume = "121",
pages = "3269--3276",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "8",

}

TY - JOUR

T1 - RhoA protects the mouse heart against ischemia/reperfusion injury

AU - Xiang, Sunny Yang

AU - Vanhoutte, Davy

AU - Del Re, Dominic P.

AU - Purcell, Nicole H.

AU - Ling, Haiyun

AU - Banerjee, Indroneal

AU - Bossuyt, Julie B C

AU - Lang, Richard A.

AU - Zheng, Yi

AU - Matkovich, Scot J.

AU - Miyamoto, Shigeki

AU - Molkentin, Jeffery D.

AU - Dorn, Gerald W.

AU - Brown, Joan Heller

PY - 2011/8/1

Y1 - 2011/8/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=79960978003&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79960978003&partnerID=8YFLogxK

U2 - 10.1172/JCI44371

DO - 10.1172/JCI44371

M3 - Article

C2 - 21747165

AN - SCOPUS:79960978003

VL - 121

SP - 3269

EP - 3276

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 8

ER -