ANGPTL2 activity in cardiac pathologies accelerates heart failure by perturbing cardiac function and energy metabolism

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.

ANGPTL2 ― A New Causal Player in Accelerating Heart Disease Development in the Aging ―

“…Furthermore, in mice, circulating ANGPTL2 concentrations increase as HF induced by transverse aorta constriction develops, related primarily to increases in heart-secreted ANGPTL2. 21 Circulating ANGPTL2 concentrations also inversely correlate with the percent of fractional shortening in mice. In mouse models of HF, inhibition of ANGPTL2 secretion by injection of AAV6-shANGPTL2 antagonizes cardiac dysfunction, 21 suggesting that cardiomyocytes are a major source of secreted ANGPTL2 in HF conditions.…”

“…Further investigation is required to determine whether increased circulating ANGPTL2 concentrations could serve as a found that increased ANGPTL2 activity induced in the pathologically stressed heart accelerated cardiac dysfunction by inactivating both AKT and sarco(endo)plasmic reticulum Ca 2+ -ATPase (SERCA)2a signaling and by decreasing myocardial energy metabolism in an autocrine/paracrine manner ( Figure 5). 21 Conversely, ANGPTL2 suppression restored cardiac function and myocardial energy metabolism, blocking pathologic remodeling. 21 It is noteworthy that this suppressive activity of ANGPTL2 on cardiac function is not attributable to its pro-inflammatory effect.…”

“…21 Conversely, ANGPTL2 suppression restored cardiac function and myocardial energy metabolism, blocking pathologic remodeling. 21 It is noteworthy that this suppressive activity of ANGPTL2 on cardiac function is not attributable to its pro-inflammatory effect. ANGPTL2 expression increases in pathologically remodeled hearts of mice and humans, but in mice, decreased cardiac ANGPTL2 expression occurs in physiologic cardiac remodeling induced by endurance training, 21 suggesting that respective activation or inactivation of heart-derived autocrine/paracrine ANGPTL2 signaling determines whether an individual will be predisposed to or protected from HF development.…”

“…22 We have also reported that ANGPTL2 expression significantly increases in the hearts of aged compared with young mice. 21 In a chemically induced skin carcinogenesis mouse model, dimethylbenzanthracene (DMBA) and phorbol 12-myristate 13-acetate (PMA) treatment reportedly induced DNA damage and cell senescence in the skin and subsequent development of cutaneous squamous cell carcinoma. 18, 64 We previously reported that ANGPTL2 expression markedly increases in the skin of DMBA/PMA-treated compared with control mice, 18 indicating that ANGPTL2 expression increases in senescent cells in parallel with DNA damage.…”

Circulating ANGPTL2 Levels Increase in Humans and Mice Exhibiting Cardiac Dysfunction

“…Recently, we reported that ANGPTL2 secreted from pathologically stressed heart accelerates cardiac dysfunction, and that suppression of ANGPTL2 production from the heart restored cardiac function and myocardial energy metabolism, thereby blocking HF development. 11, 20 In that study, although we observed increased levels of circulating ANGPTL2 in mice with cardiac dysfunction, we did not address whether ANGPTL2 affects cardiomyocytes in an endocrine or autocrine/paracrine manner. Interestingly, another study reported that circulating ANGPTL2 levels are higher in HF patients than in controls, and that cardiac function is inversely correlated with levels of ANGPTL2 circulating in the periphery, 21 although this study did not address underlying mechanisms.…”