Altered Left Ventricular Rat Gene Expression Induced by the Myosin Activator Omecamtiv Mecarbil.

To explore the impact of omecamtiv mecarbil (OM) on the gene expression profile in adult male rats. Fourteen male Wistar rats were randomly assigned to a single OM (1.2 mg/kg/h; n = 6) or placebo (n = 8) 30-min infusion. Echocardiography was performed before and after OM infusion. Seven days after infusion, rats were euthanized, and left ventricular (LV) tissues were removed for quantitative polymerase chain reaction (RTq-PCR) experiments. After OM infusion, pro-apoptotic -to- ratio was decreased, with increased and similar gene expression. The gene expression of molecules regulating oxidative stress, including glutathione disulfide reductase () and superoxide dismutases (/), remained unchanged, whereas the expression of antioxidant glutathione peroxidase () increased. While LV gene expression of key energy sensors, peroxisome proliferator activator () α and γ, AMP-activated protein kinase (), and carnitine palmitoyltransferase 1 () remained unchanged after OM infusion, and the expression of pyruvate dehydrogenase kinase 4 () increased. The LV expression of the major myocardial glucose transporter decreased, with no changes in expression, whereas the LV expression of oxidized low-density lipoprotein receptor 1 () and arachidonate 15-lipoxygenase () increased, with no changes in fatty acid transporter . An increased LV expression of angiotensin II receptors and was observed, with no changes in angiotensin I-converting enzyme expression. The Kalikrein-bradykinin system was upregulated with increased LV expression of kallikrein-related peptidases , , and and bradykinin receptors B1 and B2 ( and ), whereas the LV expression of inducible nitric oxide synthase 2 () increased. LV expression in major molecular determinants involved in calcium-dependent myocardial contraction remained unchanged, except for an increased LV expression of calcium/calmodulin-dependent protein kinase II delta () in response to OM. A single intravenous infusion of OM, in adult healthy rats, resulted in significant changes in the LV expression of genes regulating apoptosis, oxidative stress, metabolism, and cardiac contractility.