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.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 CVD 1 . In the non-diabetic population, women typically develop CVD nearly a decade later than men. However, this sex difference in CVD is not seen after menopause, leading to the notion that estrogen 'protects' women from developing CVD. Importantly, results from the 20 year Framingham Study show that diabetic women, independent of age, are at significantly higher risk of developing CVD compared to age-matched men, which suggests a deviation from the theory that women are 'protected' from CVD due to elevated estrogen 2,3 . In fact, 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. ZL males (ZL-M) and ZDF males (ZDF-M) have been extensively characterized [14][15][16][17] . While ZDF-M have similar body weights a...
Objective Resistance to obesity is observed in rodents and humans treated with Rapamycin (Rap) or Nebivolol (Neb). Since cardiac miR-208a promotes obesity, we tested whether the modes of actions of Rap and Neb involve inhibition of miR-208a. Methods Mouse cardiomyocyte HL-1 cells and Zucker obese (ZO) rats were used to investigate regulation of cardiac miR-208a. Results Angiotensin II (Ang II) increased miR-208a expression in HL-1 cells. Pre-treatment with an AT1 receptor (AT1R) antagonist, losartan (1µM), antagonized this effect, whereas a phospholipase C inhibitor, U73122 (10µM) and an NADPH oxidase inhibitor, apocynin (0.5mM) did not. Ang II-induced increase in miR-208a was suppressed by Rap (10nM), an inhibitor of nutrient sensor kinase mTORC1, and Neb (1µM), a 3rd generation β-blocker that suppressed bioavailable AT1R binding of 125I-Ang II. Thus, suppression of AT1R expression by Neb, inhibition of AT1R activation by losartan, and inhibition of AT1R-induced activation of mTORC1 by Rap attenuated the Ang II-induced increase in miR-208a. In ZO rats, Rap treatment (750µg/kg/day; 12 weeks) reduced obesity despite similar food intake, suppressed cardiac miR-208a, and increased cardiac MED13, a suppresser of obesity. Conclusion Rap and Neb suppress cardiac miR-208a. MiR-208a suppression and increase in MED13 correlated with attenuated weight gain despite leptin resistance.
We tested the hypothesis that loss of Nlrp3 would protect mice from Western diet-induced adipose tissue (AT) inflammation and associated glucose intolerance and cardiovascular complications. Five-week old C57BL6J wild-type (WT) and Nlrp3 knockout (Nlrp3-/-) mice were randomized to either a control diet (10% kcal from fat) or Western diet (45% kcal from fat and 1% cholesterol) for 24 weeks (n = 8/group). Contrary to our hypothesis that obesity-mediated white AT inflammation is Nlrp3-dependent, we found that Western diet-induced expression of AT inflammatory markers (i.e., Cd68, Cd11c, Emr1, Itgam, Lgals, Il18, Mcp1, Tnf, Ccr2, Ccl5 mRNAs, and Mac-2 protein) were not accompanied by increased caspase-1 cleavage, a hallmark feature of NLRP3 inflammasome activation. Furthermore, Nlrp3 null mice were not protected from Western diet-induced white or brown AT inflammation. Although Western diet promoted glucose intolerance in both WT and Nlrp3-/- mice, Nlrp3-/- mice were protected from Western diet-induced aortic stiffening. Additionally, Nlrp3-/- mice exhibited smaller cardiomyocytes and reduced cardiac fibrosis, independent of diet. Collectively, these findings suggest that presence of the Nlrp3 gene is not required for Western diet-induced AT inflammation and/or glucose intolerance; yet Nlrp3 appears to play a role in potentiating arterial stiffening, cardiac hypertrophy and fibrosis.
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