Losartan counteracts the effects of cardiomyocyte swelling on glucose uptake and insulin receptor substrate-1 levels

Abstract

A growing body of evidence demonstrates an association between Angiotensin II (Ang II) receptor blockers (ARBs) and enhanced glucose metabolism during ischemic heart disease. Despite these encouraging results, the mechanisms responsible for these effects during ischemia remain poorly understood. In this study we investigated the influence of losartan, an AT1 receptor blocker, and secreted Ang II (sAng II) on glucose uptake and insulin receptor substrate (IRS-1) levels during cardiomyocyte swelling. H9c2 cells were differentiated to cardiac muscle and the levels of myogenin, Myosin Light Chain (MLC), and membrane AT1 receptors were measured using flow cytometry. Intracellular Ang II (iAng II) was overexpressed in differentiated cardiomyocytes and swelling was induced after incubation with hypotonic solution for 40 min. Glucose uptake and IRS-1 levels were monitored by flow cytometry using 2-NBDG fluorescent glucose (10 μM) or an anti-IRS-1 monoclonal antibody in the presence or absence of losartan (10−7 M). Secreted Angiotensin II was quantified from the medium using a specific Ang II-EIA kit. To evaluate the relationship between sAng II and losartan effects on glucose uptake, transfected cells were pretreated with the drug for 24 hours and then exposed to hypotonic solution in the presence or absence of the secreted peptide. The results indicate that: (1) swelling of transfected cardiomyocytes decreased glucose uptake and induced the secretion of Ang II to the extracellular medium; (2) losartan antagonized the effects of swelling on glucose uptake and IRS-1 levels in transfected cardiomyocytes; (3) the effects of losartan on glucose uptake were observed during swelling only in the presence of sAng II in the culture medium. Our study demonstrates that both losartan and sAng II have essential roles in glucose metabolism during cardiomyocyte swelling.

Capillary pruning couples tissue perfusion and oxygenation with cardiomyocyte maturation in the postnatal mouse heart

“…Electrocardiogram analysis at P7 (after treatment) showed a mild acceleration of heart rate in mice treated with losartan or prazosin (Supplementary Figure S6B; Supplementary Table S3), as expected after vasodilator administration, and no significant changes in atrial conductance (P wave, PR interval) but a significantly shorter normalized QRS complex (Supplementary Figure S6B; Supplementary Table S3). Given that the in vitro effects reported for losartan and prazosin on metabolism, mitochondria, contractility or conductance of cardiomyocytes (Luo et al, 2001;Xu et al, 2009;Pennanen et al, 2014;Gerena et al, 2017) do not fully align with those we observed in vivo, our data suggest that treatment of neonatal mice with losartan or prazosin results in defective cardiac ventricular contractility and accelerated electrical conductivity, at least in part by affecting capillary pruning and cardiomyocyte maturation.…”