OBG-like ATPase 1 inhibition attenuates angiotensin II-induced hypertrophic response in human ventricular myocytes via GSK-3beta/beta-catenin signalling.

Abstract

Obg-like ATPase 1 (OLA1) that possesses both GTP and ATP hydrolyzing activities has been shown to be involved in translational regulation of cancer cell growth and survival. Also, GSK3β signalling has been implicated in cardiac development and disease. However, the role of OLA1 in pathological cardiac hypertrophy is unknown. We sought to understand the mechanism by which OLA1 regulates GSK3β-β-Catenin signalling and its functional significance in angiotensin-II (ANG II)-induced cardiac hypertrophic response. OLA1 function and its endogenous interaction with GSK3β/β-catenin signalling in cultured human ventricular cardiomyocytes (AC16 cells) and mouse hearts (in vivo) was evaluated with/without ANG II-stimulated hypertrophic response. ANG II administration in mice increases myocardial OLA1 protein expression with a corresponding increase in GSK3β phosphorylation and decrease in β-Catenin phosphorylation. Cultured cardiomyocytes treated with ANG II show endogenous interaction between OLA1 and GSK3β, nuclear accumulation of β-Catenin and significant increase in cell size and expression of hypertrophic marker genes such as atrial natriuretic factor (ANF; NPPA) and β-myosin heavy chain (MYH7). Intriguingly, OLA1 inhibition attenuates the above hypertrophic response in cardiomyocytes. Taken together, our data suggest that OLA1 plays a detrimental role in hypertrophic response via GSK3β/β-catenin signalling. Translation strategies to target OLA1 might potentially limit the underlying molecular derangements leading to left ventricular dysfunction in patients with maladaptive cardiac hypertrophy.

• Authors: Gayathri Narasimhan, John Henderson, Hien T Luong, Namakkal Soorapan Rajasekaran, Gangjian Qin, Jianyi Zhang, Prasanna Krishnamurthy
• Journal: Clinical and experimental pharmacology & physiology (Clin Exp Pharmacol Physiol) Vol. 46 Issue 8 Pg. 743-751 (08 2019) ISSN: 1440-1681 [Electronic] Australia
• PMID: 31063653 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 John Wiley & Sons Australia, Ltd.

Chemical References

• Enzyme Inhibitors
• beta Catenin
• Angiotensin II
• Glycogen Synthase Kinase 3 beta
• Adenosine Triphosphatases
• GTP-Binding Proteins
• OLA1 protein, human

Topics

• Adenosine Triphosphatases (antagonists & inhibitors)
• Angiotensin II (pharmacology)
• Animals
• Cardiomegaly (chemically induced, drug therapy, pathology)
• Cell Line
• Enzyme Inhibitors (pharmacology, therapeutic use)
• GTP-Binding Proteins (antagonists & inhibitors)
• Glycogen Synthase Kinase 3 beta (metabolism)
• Heart Ventricles (pathology)
• Humans
• Mice
• Mice, Inbred C57BL
• Myocytes, Cardiac (drug effects, pathology)
• Signal Transduction (drug effects)
• Up-Regulation (drug effects)
• beta Catenin (metabolism)