The prevalence of diastolic dysfunction sharply increases in women after menopause and may lead to heart failure, for which there are no proven treatments. While evidence suggests that estrogen may protect the premenopausal heart from hypertension and ventricular remodeling, the mechanisms involved are not understood. The newly recognized G protein-coupled estrogen receptor, GPR30, may protect postmenopausal women from cardiovascular disease. However, appropriate animal models need to be established and refined to better understand how activation of cardiac GPR30 might reduce the likelihood of diastolic dysfunction and its progression to diastolic heart failure in oler women. The primary objective of this pilot research study is two-fold: first, to generate and characterize the cardiomyocyte-specific, doxycycline-inducible GPR30 knockout mouse and second, to determine the molecular, histological, and functional roles of GPR30 in hearts from adult female mice exposed to chronic hemodynamic overload induced by transverse aortic constriction. To attain this objective, we will test the working hypothesis thatin the absence of cardiac GPR30, impairments in myocardial relaxation, left ventricular chamber compliance, exercise tolerance and left ventricular remodeling are accelerated compared to age-matched GPR30-intact littermates exposed to the same perturbation. We will test our hypothesis utilizing a new rodent model that involves the Cre/loxP gene knockout methodology, coupled with non-invasive and invasive in vivo assessments of cardiac function, structure and hemodynamics in the female cardiomyocyte-specific, doxycycline-inducible GPR30 knockout mouse. The ability to spatially (cardiac tissue only) and temporally regulate GPR30 gene expression is critical when establishing experimental models that mimic the dynamic ovarian hormone milieu of aging women. Successful completion of the proposed research will contribute a missing, fundamental element to our existing knowledge, without which we cannot understand the cardio-specific role of GPR30 inactivation in accelerated cardiac aging of postmenopausal women. This knowledge will be important in testing GPR30-related molecular mechanisms behind the development and progression of sex-specific diastolic dysfunction, and to test new therapeutic strategies. When the proposed studies have been completed, it is our expectation that 1) we will fully characterize the molecular, histological, ad functional cardiac phenotype of the cardiomyocyte-specific, doxycycline-inducible GPR30 knockout mouse, and 2) we will identify, in our unique model, whether the unfavorable structural and functional features (specifically, diastolic dysfunction, reduced exercise capacity, and left ventricular remodeling) of deleting GPR30 in female mice are initiated and/or exacerbated by experimentally-induced pressure overload. Such a finding would allow development of much-needed therapeutic approaches, such as GPR30 activation, to be temporally initiated to prevent the progression of accelerated cardiac aging, or diastolic dysfunction, after menopause or the onset of systolic hypertension.
Diastolic dysfunction is prevalent among older women and antedates heart failure, for which there is no proven treatment. These studies will test the use of a new mouse model to define the cardiac-specific role of the novel G protein-coupled estrogen receptor, GPR30, in the female heart. The proposed project could lead to much-needed improved pharmacological interventions for cardiac disease prevention and therapy in aging women.
|Ahmad, Sarfaraz; Varagic, Jasmina; Groban, Leanne et al. (2014) Angiotensin-(1-12): a chymase-mediated cellular angiotensin II substrate. Curr Hypertens Rep 16:429|
|Zhao, Zhuo; Wang, Hao; Jessup, Jewell A et al. (2014) Role of estrogen in diastolic dysfunction. Am J Physiol Heart Circ Physiol 306:H628-40|