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

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

Shelby A Dahlen, Ipsita Mohanty, Ursula Djameh, Alethia Edwards, Jennifer Koch and Patrick Osei Owusu
Hypertension (Dallas, Tex. 1979), v 72(Suppl_1)
Sep 2018
DOI: https://doi.org/10.1161/hyp.72.suppl_1.010

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.

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