Abstract
Rapamycin (Rap) is a widely-used drug in organ transplant prophylaxis, drug eluting stents to prevent coronary restenosis, and cancer therapy. Rap is also considered as an anti-aging drug that improves health and life-span. However, evidence also suggests that new-onset diabetes mellitus (DM) is an adverse outcome of Rap treatment. Since DM is an independent risk factor for heart disease, it is unclear whether chronic Rap treatment would be beneficial or detrimental for myocardium. To test the hypothesis that chronic Rap treatment would have differential effects on cardiac pathology in lean and obese insulin resistant individuals, we investigated the effect of 12-week Rap treatment (via subcutaneous implantation of Rap pellets delivering Rap at a concentration of 750μg/kg/day) on young (8-20 weeks), Zucker lean (ZL) rats and insulin resistant Zucker obese (ZO) rats. While Rap treatment significantly suppressed body weight, heart weight, fasting plasma levels of cholesterol, triglycerides, and LDL in ZO rats (p<0.05), it also worsened DM as indicated by severe hyperglycemia, polydipsia and polyuria (p<0.05). Conversely, Rap-treated ZL rats did not develop DM. Echocardiography showed that 14-week old ZO rats exhibited abnormalities in diastolic parameters, including decreases in the tissue doppler E’/A’ ratio, mitral inflow propagation velocity (Vp) indicative of impaired active phase relaxation, as well as increases in LV filling pressure (E/E’ and E/Vp ratios), isovolumic relaxation time (IVRT) and myocardial performance index (Tei index of global cardiac function) compared to age-matched ZL rats. With the exception of IVRT, these abnormalities were improved in ZO rats treated for 6 weeks with Rap. However, an additional 6 weeks of Rap treatment reversed this improvement in diastolic abnormalities. IVRT, Vp and E/Vp ratio tended to be more impaired in ZO rats with 12 week Rap treatment, although none of the trends reached statistical significance. Histopathology analysis revealed that Rap treatment induced significant cardiomyofibril disarray in both ZL and ZO rats (p<0.05). These observations suggest that Rap treatment advances DM in obese, insulin resistant rats and induces cardiac structural damage in both healthy and obese rats.
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