Abstract 14567: Caveolin-1 Deficiency Exacerbates Cardiac Dysfunction and Reduces Survival in Mice with Myocardial Infarction
Background: Caveolin-1 (Cav-1), the principal protein of caveolar domains, has previously been involved in the pathogenesis of ischemic injuries. For instance, modulations of endogenous Cav-1 expression have been reported in animal models of ischemic acute renal failure, myocardial infarction and cerebral ischemia/reperfusion. Furthermore, ablation of the Cav-1 gene in mice was shown to increase the extent of ischemic injury in models of cerebral and hindlimb ischemia. Cav-1 was also recently suggested to be involved in myocardial ischemic preconditioning. However, the role of Cav-1 in myocardial ischemia (MI)-induced cardiac dysfunction still remains to be determined.
Methods: Eight week-old wild-type (WT) and Cav-1 knockout (KO) FVB/N male mice were subjected to either sham surgery or permanent left anterior descending (LAD) coronary artery ligation for 24 hours. The progression of myocardial ischemic injury was monitored by transthoracic echocardiography, hemodynamic measurements, 2,3,5-triphenyltetrazolium chloride (TTC) staining, beta-binding analysis, cAMP level measurements and Western blot analyses.
Results: WT and Cav-1 KO mice subjected to sham surgery display similar cardiac function as indicated by comparable left ventricular (LV) ejection fraction, fractional shortening and end-diastolic pressures (LVEDP). However, Cav-1 KO mice subjected to permanent LAD ligation display reduced survival as compared to WT mice subjected to the same procedure. Interestingly, despite similar infarct sizes, Cav-1 KO mice subjected to MI show reduced LV ejection fraction and fractional shortening as well as increased LVEDP as compared to their WT counterparts. Mechanistically, Cav-1 KO mice subjected to MI exhibit reduced beta-adrenergic receptor plasma membrane density, cAMP levels and protein kinase A (PKA) phosphorylation.
Conclusions: Ablation of the Cav-1 gene exacerbates cardiac dysfunction and reduces survival in mice subjected to MI. Mechanistically, Cav-1 KO mice subjected to permanent LAD ligation display abnormalities in beta-adrenergic signaling.
- © 2010 by American Heart Association, Inc.