Abstract
Population studies have shown that compared to diabetic men, diabetic women are at a higher risk of cardiovascular disease. However, the mechanisms underlying this gender disparity are unclear. Our studies in young murine models of type 2 diabetes mellitus (T2DM) and cardiovascular disease show that diabetic male rats develop increased cardiac fibrosis and suppression of intracardiac anti-fibrotic cytokines, while premenopausal diabetic female rats do not. This protection from cardiac fibrosis in female rats can be an estrogen-related effect. However, diabetic female rats develop early subclinical myocardial deformation, cardiac hypertrophy via elevated expression of pro-hypertrophic miR-208a, myocardial damage, and suppression of cardio-reparative Angiotensin II receptor 2 (Agtr2). Diabetic rats of both sexes exhibit a reduction in cardiac capillary density. However, diabetic female rats have reduced expression of neuropilin 1 that attenuates cardiomyopathy compared to diabetic male rats. A combination of cardiac hypertrophy and reduced capillary density likely contributed to increased myocardial structural damage in diabetic female rats. We propose expansion of existing cardiac assessments in diabetic female patients to detect myocardial deformation, cardiac hypertrophy and capillary density via non-invasive imaging, as well as suggest miR-208a, AT2R and neuropilin 1 as potential therapeutic targets and mechanistic biomarkers for cardiac disease in females.
Highlights
Extensive clinical observations over the past decade have linked diabetes to cardiovascular disease (CVD) and concluded that an estimated 70% of the diabetic population die from CVD1
Zucker diabetic fatty (ZDF)-F were severely hyperinsulinemic throughout the study, insulin levels slightly dropped at the age of 17-weeks (Fig. 2b)
We report that ZDF females (ZDF-F) exhibited concentric cardiac hypertrophy and remodeling at 3-months (Fig. 3), and this cardiac hypertrophy persisted at 5-months (Fig. 8a)
Summary
Extensive clinical observations over the past decade have linked diabetes to cardiovascular disease (CVD) and concluded that an estimated 70% of the diabetic population die from CVD1. In the non-diabetic population, women typically develop CVD nearly a decade later than men. Subsequent long-term clinical studies show that diabetic women are an increased risk-group for CVD compared to age-matched non-diabetic women and diabetic men[4,5,6,7,8,9,10,11,12,13]. The mechanisms underlying the increased CVD risk in diabetic women and their poorer outcomes, compared to their male counterparts, are unknown and require further characterization. In order to investigate these mechanisms, as well as better characterize the biological sex-based differences in diabetes and CVD development, we compared several key cardiac functional and metabolic parameters between four cohorts comprised of healthy male and female Zucker Lean (ZL) rats and hyperglycemic male and female Zucker diabetic fatty (ZDF) rats.
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