Dahlen Shelby, Mohanty Ipsita, Sun Bo, Nallapaneni Sanjana, Osei-Owusu Patrick
Department of Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Department of Pharmacology & Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
Physiol Rep. 2025 Jan;13(1):e70178. doi: 10.14814/phy2.70178.
Sympathoexcitation is a hallmark of heart failure, with sustained β-adrenergic receptor (βAR)-G protein signaling activation. βAR signaling is modulated by regulator of G protein signaling (RGS) proteins. Previously, we reported that Gα regulation by RGS2 or RGS5 is key to ventricular rhythm regulation, while the dual loss of both RGS proteins results in left ventricular (LV) dilatation and dysfunction. Here, we tested whether sustained βAR stimulation with isoproterenol (ISO, 30 mg/kg/day, 3 days) exacerbates LV remodeling in male mice with germline deletion of Rgs2 and/or Rgs5. Rgs2 KO and Rgs2/5 dbKO mice showed LV dilatation at baseline, which was unchanged by ISO. Rgs2 or Rgs5 deletion decreased Rgs1 expression, whereas Rgs5 deletion increased Rgs4 expression. ISO induced cardiac hypertrophy and interstitial fibrosis in Rgs2/5 dbKO mice without increasing cardiomyocyte size or LV dilation but increased expression of cardiac fetal gene Nppa, α-actinin, and Ca-/calmodulin-dependent kinase II. Single Rgs2 and Rgs5 KO mice had markedly increased CD45 cells, whereas tissue from Rgs5 KO mice showed increased CD68 cells, as revealed by immunohistochemistry. The results together indicate that ventricular remodeling due to Rgs2 and/or Rgs5 deletion is associated with augmented myocardial immune cell presence but is not exacerbated by sustained βAR stimulation.
交感神经兴奋是心力衰竭的一个标志，伴有持续的β-肾上腺素能受体（βAR）-G蛋白信号激活。βAR信号由G蛋白信号调节剂（RGS）蛋白调节。此前，我们报道RGS2或RGS5对Gα的调节是心室节律调节的关键，而这两种RGS蛋白的双重缺失会导致左心室（LV）扩张和功能障碍。在此，我们测试了用异丙肾上腺素（ISO，30mg/kg/天，3天）持续刺激βAR是否会加剧Rgs2和/或Rgs5种系缺失的雄性小鼠的左心室重塑。Rgs2基因敲除（KO）和Rgs2/5双基因敲除（dbKO）小鼠在基线时出现左心室扩张，ISO对此无影响。Rgs2或Rgs5缺失会降低Rgs1表达，而Rgs5缺失会增加Rgs4表达。ISO在Rgs2/5 dbKO小鼠中诱导心脏肥大和间质纤维化，但不增加心肌细胞大小或左心室扩张，却增加了心脏胎儿基因Nppa、α-辅肌动蛋白和钙/钙调蛋白依赖性激酶II的表达。单Rgs2和Rgs5基因敲除小鼠的CD45细胞明显增加，而免疫组化显示Rgs5基因敲除小鼠的组织中CD68细胞增加。这些结果共同表明，由于Rgs2和/或Rgs5缺失导致的心室重塑与心肌免疫细胞增多有关，但不会因持续的βAR刺激而加剧。
