Open AccessPressure-overload-induced angiotensin-mediated early remodeling in mouse heart
Author(s) -
Jeremy H. Kim,
Yaping Jiang,
Ira S. Cohen,
Richard Z. Lin,
Richard T. Mathias
Publication year - 2017
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0176713
Subject(s) - angiotensin ii , medicine , pressure overload , muscle hypertrophy , endocrinology , ventricle , myocyte , contractility , ventricular remodeling , saralasin , chemistry , heart failure , biology , receptor , cardiac hypertrophy
Our previous work on angiotensin II-mediated electrical-remodeling in canine left ventricle, in connection with a long history of other studies, suggested the hypothesis: increases in mechanical load induce autocrine secretion of angiotensin II (A2), which coherently regulates a coterie of membrane ion transporters in a manner that increases contractility. However, the relation between load and A2 secretion was correlative. We subsequently showed a similar or identical system was present in murine heart. To investigate whether the relation between mechanical load and A2-mediated electrical remodeling was causal, we employed transverse aortic constriction in mice to subject the left ventricle to pressure overload for short-term (1 to 2 days) or long-term (1 to 2 weeks) periods. Heart-to-body weight ratios and cell capacitance measurements were used to determine hypertrophy. Whole-cell patch clamp recordings of the predominant repolarization currents I to,fast and I K,slow were used to assess electrical remodeling. Hearts or myocytes subjected to long-term load displayed significant hypertrophy, which was not evident in short-term load. However, short-term load induced significant reductions in I to,fast and I K,slow . Incubation of these myocytes with the angiotensin II type 1 receptor inhibitor saralasin for 2 hours restored I to,fast and I K,slow to control levels. The number of I to.fast or I K,slow channels did not change with A2 or long-term load, however the hypertrophic increase in membrane area reduced the current densities for both channels. For I to,fast but not I K,slow there was an additional reduction that was reversed by inhibition of angiotensin receptors. These results suggest increased load activates an endogenous renin angiotensin system that initially reduces I to,fast and I K,slow prior to the onset of hypertrophic growth. However, there are functional interactions between electrical and anatomical remodeling. First, hypertrophy tends to reduce all current densities. Second, the hypertrophic program can modify signaling between the angiotensin receptor and target current.