Abstract 010: Dual Loss of RGS2 and 5 Exacerbates the Progression of Cardiac Hypertrophy in Mice Chronically Treated With Isoproterenol

Abstract

This study determined the effect of chronic isoproterenol (ISO) treatment on cardiac structure and function in male mice without or with dual loss of regulator of G protein signaling (RGS) 2 and 5. RGS2 and 5 act as GTPase-activating proteins (GAPs) that preferentially terminate signaling via G q/11 - and G i/o class G proteins, by accelerating GTP hydrolysis. Deletion of either RGS2 or 5 increases susceptibility to cardiovascular disease. However, the effects of dual absence of the two RGS proteins on normal physiology and disease are unknown. Using mice concurrently lacking RGS2 and 5 ( Rgs2/5 dbKO) and wild type (WT) cohort, we determined how the dual absence of both RGS proteins affects cardiac response to chronic β-adrenergic receptor stimulation. WT and Rgs2/5 dbKO mice were infused with saline or 30 μg/g/day of ISO for 3 or 14 days. At baseline, Rgs2/5 dbKO mice showed cardiac hypertrophy (WT: 9.06 ± 0.34 vs. dbKO: 10.16 ± 0.32 mg/mm tibia length; p <0.05) and left ventricular chamber dilation by echocardiography, without tissue fibrosis. ISO infusion for 3 days caused and augmented cardiac hypertrophy in WT (SAL: 9.65 ± 0.38 vs. ISO: 11.68 ± 0.45 mg/mm tibia length; p <0.05) and Rgs2/5 dbKO (SAL: 9.97 ± 0.43 vs. ISO: 12.57 ± 0.69 mg/mm tibia length; p <0.01) mice, respectively, as well as interstitial fibrosis and increased expression of hypertrophic and heart failure gene markers, including Nppa , Serca , Mybpc3 and Tnni3 . Sub-chronic ISO infusion also caused a greater decrease in percent fractional shortening by day 3, in Rgs2/5 dbKO relative to WT mice (WT: -4.22 ± 4.15 vs. dbKO: -7.69 ± 3.86 %; p <0.05). In WT mice, cardiac hypertrophy and left ventricular dilation were lower after 14-day compared to 3-day ISO infusion, but similar to saline-treated control levels (ΔSAL to 3d-ISO: 21.04 ± 0.82 vs. ΔSAL to 14d-ISO: 15.05 ± 0.66 %; p <0.05). This was accompanied by a robust increase in Rgs5 but not Rgs2 mRNA expression in WT mice. In contrast, Rgs2/5 dbKO mice continued to show abnormal cardiac structure and function after 14-day ISO infusion. Together, these data suggest that increased expression of RGS5 compensates for the lack of change in RGS2 expression and/or function and protects against transition from ISO-induced cardiac hypertrophy to heart failure.