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

被引：1

作者：

El Oumeiri, Bachar ^{[1
]}

Dewachter, Laurence ^{[2
]}

Van de Borne, Philippe ^{[3
]}

Hubesch, Geraldine ^{[2
]}

Melot, Christian ^{[2
]}

Jespers, Pascale ^{[2
]}

Stefanidis, Constantin ^{[1
]}

Mc Entee, Kathleen ^{[2
]}

Vanden Eynden, Frederic ^{[1
]}

机构：

[1] Univ Libre Bruxelles ULB, Dept Cardiac Surg, Erasme Univ Hosp, B-1070 Brussels, Belgium

[2] Univ Libre Bruxelles ULB, Fac Med, Lab Physiol & Pharmacol, B-1070 Brussels, Belgium

[3] Univ Libre Bruxelles ULB, Dept Cardiol, Erasme Univ Hosp, B-1070 Brussels, Belgium

来源：

GENES | 2023年 / 14卷 / 01期

关键词：

left ventricle; omecamtiv mecarbil; gene expression; apoptosis; metabolism; oxidative stress; NITRIC-OXIDE SYNTHASE; BETA-ADRENERGIC STIMULATION; HEART-FAILURE; ENDOTHELIAL RECEPTOR; INCREASES; LOX-1; PHARMACOLOGY; INFLAMMATION; CONTRIBUTES; SENSITIVITY;

D O I：

10.3390/genes14010122

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 real-time quantitative polymerase chain reaction (RTq-PCR) experiments. After OM infusion, pro-apoptotic Bax-to-Bcl2 ratio was decreased, with increased Bcl2 and similar Bax gene expression. The gene expression of molecules regulating oxidative stress, including glutathione disulfide reductase (Gsr) and superoxide dismutases (Sod1/Sod2), remained unchanged, whereas the expression of antioxidant glutathione peroxidase (Gpx) increased. While LV gene expression of key energy sensors, peroxisome proliferator activator (Ppar) alpha and gamma, AMP-activated protein kinase (Ampk), and carnitine palmitoyltransferase 1 (Cpt1) remained unchanged after OM infusion, and the expression of pyruvate dehydrogenase kinase 4 (Pdk4) increased. The LV expression of the major myocardial glucose transporter Glut1 decreased, with no changes in Glut4 expression, whereas the LV expression of oxidized low-density lipoprotein receptor 1 (Olr1) and arachidonate 15-lipoxygenase (Alox15) increased, with no changes in fatty acid transporter Cd36. An increased LV expression of angiotensin II receptors AT1 and AT2 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 Klk8, Klk1c2, and Klk1c12 and bradykinin receptors B1 and B2 (Bdkrb1 and Bdkrb2), whereas the LV expression of inducible nitric oxide synthase 2 (Nos2) 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 (Cacna1c) 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.

引用

页数：15