Abstract P2027: Chronic β-Adrenergic Receptor Stimulation Exacerbates Left Ventricular Dilation And Myocardial Cell Death In Rgs2 Knockout Mice

Abstract

Sustained sympathoexciation and increased circulating catecholamine level are hallmarks of congestive heart failure. Elevated catecholamine level promotes a sustained β -adrenergic receptor (βAR) stimulation in the myocardium, altering the balance between cell death and survival via intracellular signaling downstream of G s - and G i/o -class G proteins. Previously, we and others reported that moderation of Gα i activity by regulators of G protein signaling (RGS) 2 and 5 separately is key to maintaining normal ventricular rhythm. Here, using single isogenic wild type (WT), Rgs2 -/- , Rgs5 -/- , and Rgs2/5 double knockout (dbKO) adult male mice with or without systemic isoproterenol infusion, we determined whether a compensatory relationship between RGS2 and RGS5 is cardioprotective and promotes myocardial cell survival during chronic sympathoexcitation. We found that basal heart weight-to-tibia-length (HW/TL) ratio of both Rgs2 and dbKO mice was elevated relative to WT control. Echocardiography revealed left ventricular dilation in all three KO genotypes, as evidenced by increased left ventricular internal diameter and volume. Both Rgs2 -/- and Rgs5-/- mice displayed reduced ejection fraction and fractional shortening. To explore the mechanism mediating the LV dilation, we challenged the mice with chronic βAR stimulation by systemic isoproterenol infusion (ISO, 30 mg/kg/day) for 3 or 14 days via subcutaneous osmotic mini-pumps. ISO infusion substantially increased HW/TL ratio in WT mice after day 3, while HW/TL ratio in Rgs2 -/- and dbKO mice was increased with exacerbated LV dilation. After 14-day ISO infusion, only dbKO mice displayed increased lung weight/TL ratio, indicating a congestive heart failure. Additionally, myocardial tissue from saline treated dbKO mice had a larger number of TUNEL + cells that was further increased by ISO infusion, with extensive interstitial fibrosis as visualized with Masson trichrome staining, and increased expression of heart failure biomarkers Mybpc3 and Tnni3 . Taken together, we conclude that the loss of R gs2, more-so than Rgs5, predisposes to myocardial cell death and rapid progression to dilated cardiomyopathy and heart failure during sustained sympathoexciation and β-adrenergic stimulation.