Abstract 80: Cardiac Fibroblast GRK2 Deletion Enhances Contractility and Remodeling following Ischemia/Reperfusion Injury
Decades of research have identified G Protein Coupled Receptor Kinase 2 (GRK2) as an important molecule that is upregulated in the cardiomyocyte after myocardial injury and during heart failure development. Research from our lab has convincingly demonstrated that myocyte-specific loss of GRK2 both before and after myocardial ischemic injury improves cardiac function and remodeling. Recent studies have reported that GRK2 is also upregulated in the cardiac fibroblast in the failing heart, suggesting a potential role for this molecule in the most abundant cell type in the heart. However, the in vivo implications of GRK2 expression in the fibroblast following cardiac stress remain a mystery. Tamoxifen inducible, fibroblast-specific GRK2 knockout mice (Col1α2CreER/GRK2flox) were treated with tamoxifen along with their control murine counterparts (GRK2flox alone) for 10 days to induce deletion of GRK2 in fibroblasts. Two weeks later mice were subjected to ischemia/reperfusion (I/R) injury via coronary artery occlusion for 30 minutes followed by periods of reperfusion. Fibroblast GRK2 knockout mice presented with preserved cardiac function 24 hours post-I/R compared to control mice as demonstrated by increased ejection fraction (58.1±1.8% vs. 48.7±1.2%, respectively, N=11-14, p=0.0005). GRK2 knockout mice also presented with decreased fibrosis in the infarcted area 72 hours following I/R injury as shown by Masson’s Trichrome staining. In line with decreased fibrosis, these mice also expressed decreased amounts of TGFβ1 and Collagen I. Additionally, α-smooth muscle actin expression is significantly diminished, indicating reduced fibroblast to myofibroblast transformation. These data suggest that GRK2 plays a key role up-stream in fibroblast activation and function in the ischemic heart and indicate that, like in the cardiomyocyte, inhibition of GRK2 in the cardiac fibroblast is a potential therapeutic target to limit cardiac dysfunction and remodeling after ischemic injury.
Author Disclosures: M.C. Woodall: None B.P. Woodall: None E. Gao: None X. Shang: None A. Yuan: None J. Ibetti: None W.J. Koch: None.
- © 2014 by American Heart Association, Inc.