Abstract
A cardioprotective response that alters ventricular contractility or promotes cardiomyocyte enlargement occurs with increased workload in conditions such as hypertension. When that response is excessive, pathological cardiac remodelling occurs, which can progress to heart failure, a leading cause of death worldwide. Mechanisms underlying this response are not fully understood. Here, we report that expression of angiopoietin-like protein 2 (ANGPTL2) increases in pathologically-remodeled hearts of mice and humans, while decreased cardiac ANGPTL2 expression occurs in physiological cardiac remodelling induced by endurance training in mice. Mice overexpressing ANGPTL2 in heart show cardiac dysfunction caused by both inactivation of AKT and sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a signalling and decreased myocardial energy metabolism. Conversely, Angptl2 knockout mice exhibit increased left ventricular contractility and upregulated AKT-SERCA2a signalling and energy metabolism. Finally, ANGPTL2-knockdown in mice subjected to pressure overload ameliorates cardiac dysfunction. Overall, these studies suggest that therapeutic ANGPTL2 suppression could antagonize development of heart failure.
Highlights
A cardioprotective response that alters ventricular contractility or promotes cardiomyocyte enlargement occurs with increased workload in conditions such as hypertension
Using an alternate model of heart failure (HF) based on Angiotensin II (Ang II) administration, we observed that angiopoietin-like protein 2 (ANGPTL2) protein levels in stressed heart tissues resulting from Ang II infusion significantly increased relative to vehicle-infusion controls (Fig. 1b)
Others reported that circulating ANGPTL2 levels in HF patients were higher than in control individuals, and that cardiac function was inversely correlated with levels of ANGPTL2 circulating in the periphery[36]
Summary
A cardioprotective response that alters ventricular contractility or promotes cardiomyocyte enlargement occurs with increased workload in conditions such as hypertension. A cardioprotective response to increase left ventricular contractile ability and improve myocardial metabolism occurs with increased workload in cardiac conditions such as hypertension When this response is excessive, pathological cardiac remodelling occurs, a condition often progressing to heart failure (HF), a leading cause of death that affects more than 23 million people worldwide[1]. Angptl[2] knockout (KO) mice showed increased left ventricular contractile capacity via increases in AKT-SERCA2a signalling, myocardial energy metabolism and ATP production, all of which protected mice from HF in a pressure overload model. ANGPTL2-knockdown (KD) human-induced pluripotent stem cell (iPS)-derived cardiomyocytes showed induction of AKT-SERCA2a signalling and proper myocardial energy metabolism compared with control iPS-derived cardiomyocytes Together, these results suggest that increased ANGPTL2 activity accelerates cardiac dysfunction and that therapeutic ANGPTL2 suppression could antagonize this condition
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
