Physiopathological implications of hypertension associated with ovarian failure on cardiac morphology and function: modulating role of aerobic physical training

Abstract

The expressive reduction in ovarian hormones that results from menopause increases the risk of developing cardiovascular disease, affecting cardiac and vascular morphology and functionality. However, some women already have cardiovascular disease even before menopause, such as systemic arterial hypertension (SAH). In this case, ovarian failure in these women can trigger even more significant cardiac morphological and functional impairments. In the other hand, regular physical exercise promotes benefits to the cardiovascular system that antagonize the systemic damage promoted by the deprivation of ovarian hormones, as well as SAH, including attenuating the increase in cardiac fibrosis. On the other hand, the intracellular mechanisms involved in this process are not well defined. Our hypothesis is that the increase in fibrosis, and consequently cardiac morphofunctional damage, involves the participation of calpain-1, metalloproteinase-2 (MMP-2) and tissue inhibitors of metalloproteinases (TIMPs), associated with the expressive increase in pro-inflammatory markers. In turn, aerobic physical training would have the opposite effect, decreasing the action of these proteolytic enzymes and pro-inflammatory markers, resulting in an improvement in cardiac function. Objectives: To investigate the effects of ovarian failure on hemodynamics, morphology and cardiac function in hypertensive rats, as well as the participation of pro-inflammatory markers and the intracellular mechanisms of the proteolytic targets of calpain-1, MMP-2 and TIMPs. Additionally, we will investigate the role of aerobic physical training as a moderator of these processes. Methods: 128 18-week-old rats will be divided equally into two experimental groups (N = 64); normotensive group (Wistar-Kyoto rats) and hypertensive group (SHR, spontaneously hypertensive rats). Each group will be subdivided into four smaller groups (N=16); group submitted to ovariectomy in the 18th week of life (OVX); ovariectomized group and submitted to aerobic physical training for 14 weeks through swimming (OVXT); group undergoing sham surgery also in the 18th week of life (SHAM); and the SHAM group submitted to aerobic physical training (SHAMT). All groups will be submitted to the following experimental protocols; hemodynamic assessment through plethysmographic examination at four different times (18th, 22th, 24nd and 34th weeks of life); evaluation of cardiac morphology and functionality through echocardiographic examination at the 18th and 34th weeks of life; assessment of isolated cardiac function and coronary reactivity using the Langendorff technique; quantification of cardiac fibrosis and cardiomyocytes through histological analysis; and evaluation of the activities of calpain-1, MMP-2, TIMPs and inflammatory markers will be performed by means of gel zymography. The results of the present study will contribute to the understanding the mechanisms involved in cardiac morphofunctional adaptations resulting from the deprivation of ovarian hormones associated with hypertension, as well as to evaluate the therapeutic role of aerobic physical training. (AU)