Aims: Heart failure (HF) due to diastolic dysfunction (DD) but normal left ventricular (LV) ejection fraction (EF) is termed HF with preserved EF (HFpEF). Given its high prevalence in post-menopausal women, we hypothesized that 17{beta}-estradiol (E2) function is mechanistically linked to DD HF and investigated E2-deficiency in the etiology of DD in a mouse model. Methods: Female C57BL/6J mice were divided into one group with hypertension induced by N({omega})-nitro-L-arginine methyl ester (L) and cardiac pressure overload induced by angiotensin II (A), collectively inducing DD, and one group with sham treatment. Groups were subdivided to receive an ovariectomy (OVX) to induce estrogen-deficiency and emulate menopause or sham surgery. During the next 21 days, mice were tested for cardiac function, food intake, response to E2 agonists, gene profiling, cardiomyocyte-contractility and elasticity, and cardiac mitochondrial function. Results: OVX-associated E2-deficiency exacerbated DD in a time-dependent way without affecting EF or stroke volume, emulating a severe DD phenotype. These changes paralleled those for mitochondrial dysfunction, i.e., upregulation of genes associated with stress, energy metabolism, and fibrosis, as well as functional and structural defects in cardiomyocytes. Treatment of OVX + (L + A) with E2 or a G-protein-coupled estrogen receptor agonist normalized diastolic function, whereas estrogen receptor beta agonists did not. The OVX DD mice exhibited moderately impaired mitochondrial function, which delayed cardiomyocyte relaxation but not contraction, altered cardiac substrate utilization, reduced cardiomyocyte elasticity, increased production of reactive oxygen species, and potentiated extracellular fibrosis. Conclusions: OVX-induced E2-deficiency generates metabolic, structural, and functional changes in cardiomyocytes and the adjacent extracellular matrix, exacerbating the effects of L and A on diastolic function. This robust DD model revealed a role for E2 via ER in diastole-regulation in female mice and raised questions about similar mechanisms operative in postmenopausal women.
Pownall, H. J., Zhang, A., Liu, S., Vedula, I., Chatterjee, S., Wu, Y., Gu, J., Rodney, G. G., Kurrelmeyer, K. M., Taegtmeyer, H., Hamilton, D. J., Gupte, A. A.
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