Abstract 202: 17β-Estradiol Inhibits Eccentric Myocyte Hypertrophy in vivo and in vitro by an Estrogen Receptor Dependent Mechanism
Patterns of LV remodeling evolve differently in men and women. While men tend to develop LV dilatation, women are more likely to exhibit a pattern of concentric hypertrophy. In pressure overload models, estrogen replacement delays the onset of heart failure and limits LV hypertrophy. We sought to explore the effect of estrogen replacement on cardiomyocyte (CM) morphologic changes in a mouse pressure overload model in vivo and in growth stimulated adult rat CMs in vitro. Wild type, female, C57Bl/6J mice underwent ovariectomy followed by replacement with 17β-estradiol (E2) or placebo (P) delivered subcutaneously. Seven days (d) later, mice underwent sham operation (S) or transverse aortic constriction (TAC). After 14d, echocardiograms were performed, hearts were harvested and CMs isolated through enzymatic digestion. Images of dispersed CMs were captured and analyzed to determine length and area. In P-treated mice, TAC led to increased LV end diastolic diameter (p<0.001) and end systolic diameter (p<0.001), and decreased fractional shortening (p=0.028). E2 replacement prevented TAC-induced chamber dilatation and systolic dysfunction (all p<0.05 vs. placebo-TAC). In P-mice, TAC increased CM length by 14.3 ± 2.9% above S (p<0.01), which was inhibited by E2 (5.8 ± 1.8% p<0.05 vs. S, p<0.01 vs. P-TAC). In P-TAC, cell area increased by 37.5 ± 5.3% (p<0.01 vs. S) which was limited by E2 (21.0 ± 5.6%, p<0.01 vs. S; p<0.05 vs. P-TAC). In vitro, cultured adult rat CMs were pretreated with vehicle (V), E2 (10nM) or E2 plus the estrogen receptor (ER) antagonist, ICI-182,780 (ICI) followed by stimulation with phenylephrine (PE) for 48 hours. PE increased CM area by 40.5 ± 2.0% and CM length by 12.9 ± 1.8% (p<0.01 vs. V) which were abolished by E2 pretreatment. ICI blocked the E2-mediated inhibition of PE-induced CM growth. In summary, E2 replacement prevents pressure overload-induced LV dilatation and limits myocyte elongation. E2 similarly inhibits agonist-induced CM lengthening in vitro by an ER-dependent mechanism. Thus, E2 replacement promotes a more concentric pattern of CM hypertrophy, lending further support to the broad conclusion that sex hormones influence the patterns of CM growth.