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.
authors: Department of Pharmacology, UCSD, San Diego, California 92093-0636, USA.
authors: Sunny Yang
authors: SY
authors: Xiang
authors: Davy
authors: D
authors: Vanhoutte
authors: Dominic P
authors: DP
authors: Del Re
authors: Nicole H
authors: NH
authors: Purcell
authors: Haiyun
authors: H
authors: Ling
authors: Indroneal
authors: I
authors: Banerjee
authors: Julie
authors: J
authors: Bossuyt
authors: Richard A
authors: RA
authors: Lang
authors: Yi
authors: Y
authors: Zheng
authors: Scot J
authors: SJ
authors: Matkovich
authors: Shigeki
authors: S
authors: Miyamoto
authors: Jeffery D
authors: JD
authors: Molkentin
authors: Gerald W
authors: GW
authors: Dorn
authors: Joan Heller
authors: JH
authors: Brown
mesh_terms: D000818:Animals; D015971:Gene Expression Regulation, Enzymologic; D006321:Heart / Q000503:physiopathology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D010477:Perfusion; D010641:Phenotype; D011493:Protein Kinase C / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000502:physiology*; D020742:rhoA GTP-Binding Protein
chemical_list: D007770:L-Lactate Dehydrogenase; C089212:protein kinase D; D011493:Protein Kinase C; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein