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We reported that left ventricular (LV) dilatation after 4 weeks of isolated mitral regurgitation (MR) in the dogs is marked by extracellular matrix loss and an increase in adrenergic drive. Given that extracellular matrix proteins and their receptor integrins influence beta-adrenergic receptor (beta-AR) responses in vitro, we tested whether beta1-AR activation modulates focal adhesion (FA) signaling and LV remodeling in these same dogs with isolated MR. Normal dogs were compared with dogs with MR of a 4-week duration and with MR dogs treated with beta(1)-AR blockade (beta(1)-RB) (extended-release metoprolol succinate, 100 mg QD) that was started 24 hours after MR induction. In MR LVs, a decrease in collagen accumulation compared with normal dogs was associated with a decrease in FA kinase tyrosine phosphorylation, along with FA kinase interaction with adapter and cytoskeletal proteins, p130(Cas) and paxillin, respectively, as determined by immunoprecipitation assays. There was increased phosphorylation of stress related molecules p38 mitogen-activated protein kinase (MAPK) and Hsp27 and survival signaling kinases extracellular signal-regulated kinase 1/2 and AKT, with no evidence of cardiomyocyte apoptosis. beta(1)-RB attenuated FA signaling loss and prevented p38 MAPK, Hsp27, and AKT phosphorylation induced by MR and significantly increased LV epicardial collagen content. However, beta(1)-RB did not improve LV endocardial collagen loss or LV dilatation induced by MR. Isolated myocytes from normal and MR dog hearts treated with beta(1)- or beta(2)-AR agonists demonstrated no difference in FA kinase, p38 MAPK, Hsp27, or AKT phosphorylation. These results showed that chronic stimulation of beta(1)-AR during early compensated MR impairs FA signaling that may affect myocyte/fibroblast-extracellular matrix scaffolding necessary for LV remodeling.

circulation research

Sympathetic Activation Causes Focal Adhesion Signaling Alteration in Early Compensated Volume Overload Attributable to Isolated Mitral Regurgitation in the Dog