SmgGDS as a Crucial Mediator of the Inhibitory Effects of Statins on Cardiac Hypertrophy and Fibrosis

Abstract

The detailed molecular mechanisms of the pleiotropic effects of statins remain to be fully elucidated. Here, we hypothesized that cardioprotective effects of statins are mediated by small GTP-binding protein GDP dissociation stimulator (SmgGDS). SmgGDS +/– and wild-type (WT) mice were treated with continuous infusion of angiotensin II (Ang II) for 2 weeks with and without oral treatment with atorvastatin or pravastatin. At 2 weeks, the extents of Ang II–induced cardiac hypertrophy and fibrosis were comparable between the 2 genotypes. However, statins significantly attenuated cardiomyocyte hypertrophy and fibrosis in WT mice, but not in SmgGDS +/– mice. In SmgGDS +/– cardiac fibroblasts (CFs), Rac1 expression, extracellular signal–regulated kinases 1/2 activity, Rho-kinase activity, and inflammatory cytokines secretion in response to Ang II were significantly increased when compared with WT CFs. Atorvastatin significantly reduced Rac1 expression and oxidative stress in WT CFs, but not in SmgGDS +/– CFs. Furthermore, Bio-plex analysis revealed significant upregulations of inflammatory cytokines/chemokines and growth factors in SmgGDS +/– CFs when compared with WT CFs. Importantly, conditioned medium from SmgGDS +/– CFs increased B-type natriuretic peptide expression in rat cardiomyocytes to a greater extent than that from WT CFs. Furthermore, atorvastatin significantly increased SmgGDS secretion from mouse CFs. Finally, treatment with recombinant SmgGDS significantly reduced Rac1 expression in SmgGDS +/– CFs. These results indicate that both intracellular and extracellular SmgGDS play crucial roles in the inhibitory effects of statins on cardiac hypertrophy and fibrosis, partly through inhibition of Rac1, Rho kinase, and extracellular signal–regulated kinase 1/2 pathways, demonstrating the novel mechanism of the pleiotropic effects of statins.

Pleiotropic Effects of Statins on the Cardiovascular System

“…148 Statins decrease Rac1 levels, cardiomyocyte hypertrophy, and fibrosis in wild type mice, but not in mice that lack SmgGDS. 149 Rac1 contributes to doxorubicin-related cardiotoxicity through both a ROS-dependent and independent mechanism. 150 Finally, preoperative atorvastatin induced Rac1-mediated inhibition of NADPH in human atrial myocardium.…”

Structure-based analysis of the guanine nucleotide exchange factor SmgGDS reveals armadillo-repeat motifs and key regions for activity and GTPase binding

“…Recent studies have revealed that SmgGDS is up-regulated by statin, resulting in the nuclear transport and degradation of Rac1 (14). Additionally, SmgGDS is a crucial mediator of the inhibitory effects of statins on cardiac hypertrophy (15,16).…”

Treatment of Chronic Heart Failure With Preserved Left Ventricular Ejection Fraction in Patients With Hypertension Disease: Potential Therapeutic Role of Statines

“…При ХСН особое значение имеют плейо-тропные эффекты статинов: противовоспалительный, улучшение функции эндотелия путем усиления синтеза оксида азота, ограничение ремоделирования сердца, уменьшение оксидативного стресса [14,15]. Для больных с ХСН и сохраненной ФВ ЛЖ важна способность статинов уменьшать гипертрофию и фиброз миокарда, улучшать его диастолическую функцию [16].…”