Wednesday, May 8, 2024
5/8/2024
My research goal is to understand the pathophysiology of HFpEF (Heart Failure with preserved Ejection Fraction) and identify its therapeutic targets. Compelling evidence suggests that the pathophysiology of HFpEF in men and women is distinct, leading to differential phenotypes, responses to treatment, and a potential need for sex- specific therapeutic intervention. Studying sex differences in HFpEF is an essential step toward establishing a personalized therapeutic strategy. Women in HFpEF are typically in their postmenopausal state. Although women comprise the majority of HFpEF patients, the preclinical study of female HFpEF pathogenesis is limited due to a lack of animal models. Female mice, both cycling (premenopausal) and non-cycling (induced by ovariectomy), resist HFpEF development. One of the novelties of my proposed work is to use a new female HFpEF-like model induced by ovary-intact menopause (by VCD (Vinyl Cyclohexene Dioxide) injection) combined with metabolic stress. The VCD- postmenopausal differs from the ovariectomized (OVX) model since it retains residual ovarian stroma, analogous to natural menopause in women. VCD mice subjected to metabolic stress develop robust HFpEF phenotype. In addition to estrogen deficiency, women with natural menopause also experience relative androgen excess (RAE) due to the remaining androgen-producing capacity of the residual ovaries. Clinical studies show that a high androgen/estrogen ratio (not a low level of estrogen alone) is associated with increased cardiovascular risks in women. Androgens suppress NP (Natriuretic Peptide) production from atrial cells, a critical activator of cGMP- PKG signaling. Importantly, a deficiency of myocardial cGMP-PKG activity was reported to underlie myofilament dysfunction in HFpEF. My proposed work focuses on myofilament-based alterations that are responsible for mechanical dysfunction in HFpEF. Aim 1 will focus on sex-specific myofilament alterations. The diastolic function will be evaluated at the in vivo LV, the myocardium, and single cardiomyocyte levels. Diastolic stiffness, relaxation kinetics, crossbridge kinetics, myofilament Ca2+ sensitivity, and Ca2+ release-reuptake kinetics will be investigated. Passive sarcomere stiffness and the stiffness contribution of ECM (extracellular matrix) will be measured. Myofilament (phospho)proteomics, transcriptomics, activity assay, protein and RNA studies, etc., will investigate the signaling pathways associated with these mechanical changes. Aim 2 will elucidate the role of RAE and anti-androgens’ effect on diastolic function in postmenopausal HFpEF. The impact of RAE will be studied in 2 postmenopausal models: 1) the OVX model (low estrogens and low androgens); and 2) the VCD model (low estrogens and normal androgens). The contribution of RAE will be revealed through the inhibition of 5a-reductase (by anti-androgens). I anticipate that this proposed work will advance our knowledge of the sarcomere-based alterations in HFpEF and provide potential insight to alleviate diastolic dysfunction in a sex-specific manner.
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