Atorvastatin desensitizes β‐adrenergic signaling in cardiac myocytes via reduced isoprenylation of G‐protein γ‐subunits

Statins exert pleiotropic, cholesterol‐independent effects by reducing isoprenylation of monomeric GTPases. Here we examined whether statins also reduce isoprenylation of γ‐subunits of heterotrimeric G‐proteins and thereby affect β‐adrenergic signaling and regulation of force in cardiac myocytes. Neonatal rat cardiac myocytes (NRCM) were treated with atorvastatin (0.1–10 μmol/l; 12–48 h) and examined for adenylyl cyclase regulating G‐protein α‐ (Gα), β‐ (Gβ), and γ‐ (Gγ) subunits and cAMP accumulation. Engineered heart tissue (EHT) from NRCM was used to evaluate contractile consequences. In atorvastatin‐treated NRCM, a second band of Gγ3 with a lower apparent molecular weight appeared in cytosol and particulate fractions that was absent in vehicle‐treated NRCM, but also seen after GGTI‐298, a geranylgeranyl transferase inhibitor. In parallel, Gβ accumulated in the cytosol and total cellular content of Gαs was reduced. In atorvastatin‐treated NRCM, the cAMP‐increasing effect of isoprenaline was reduced. Likewise, the positive inotropic effect of isoprenaline was desensitized and reduced after treatment with atorvastatin. The effects of atorvastatin were abolished by mevalonate and/or geranylgeranyl pyrophosphate, but not by farnesyl pyrophosphate or squalene. Taken together, the results of this study show that atorvastatin desensitizes NRCM to β‐adrenergic stimulation by a mechanism that involves reduced isoprenylation of Gγ and subsequent reductions in the cellular content of Gαs.