Autophagy plays an important role in the maintenance of normal heart function. However, the role of autophagy in the inulin resistant and diabetic heart is not well understood. Furthermore, the upstream signaling and the downstream targets involved in cardiac autophagy regulation during obesity and type 2 diabetes mellitus (T2DM) are not fully elucidated. The aim of this study was to measure autophagic flux and to dissect the upstream and downstream signaling involved in cardiac autophagy regulation in the hearts of obese T2DM mice. Our study demonstrated that cardiac autophagic flux is suppressed in the heart of obese diabetic (ob/ob) mice due to impaired autophagosome formation. We showed that suppression of autophagy was due to sustained activation of mTOR as we could restore cardiac autophagy by inhibiting mTOR. Moreover, the novel finding of this study is that while IGF-1 receptor-mediated Akt activation contributes to cardiac hypertrophy, it is not involved in mTOR activation and autophagy suppression in obesity and T2DM. In contrast, inhibition of ERK signaling abolished mTOR activation and restored autophagy in the heart of obese diabetic (ob/ob) mice. The study identifies mechanisms regulating cardiac autophagy in obesity and T2DM that are mediated by ERK/mTOR but are distinct from Akt. The findings are of significant importance as they demonstrate for the first time the contribution of IGF-1 receptors (IGF-1R) and Akt signaling in cardiac hypertrophy but not in cardiac autophagy regulation in in obesity and T2DM.

Background Nuclear factor kappa B (NF-κB) is often implicated in contributing to the detrimental effects of cardiac injury. This ostensibly negative view of NF-κB competes with its important role in the normal host inflammatory and immune response. We have previously demonstrated that pharmacologic inhibition of NF-κB at the time of acute pressure-overload accelerates the progression of left ventricular hypertrophy (LVH) to heart failure in mice. NF-κB regulates angiogenesis and other factors responsible for compensatory reaction to intracellular hypoxia. We hypothesized that impaired angiogenesis may be the trigger, not the result, of pathologic LVH through NF-κB related pathways. Methods and Results Transgenic mice (KO) were generated with cardiomyocyte (CMC)-specific deletion of the p65 subunit of NF-κB. Mice underwent transverse aortic constriction and serially followed with echocardiography for 6 weeks. CMC p65 NF-κB deletion promoted maladaptive LVH and accelerated progression towards heart failure, as measured by ejection fraction, LV mass, and lung congestion. Transgenic mice had higher levels of fibrosis and periostin expression. Whole-field digital microscopy revealed increased capillary domain areas in KO mice while concurrently demonstrating decreased microvessel density. This observation was associated with decreased expression of hypoxia-inducible factor 1α (HIF-1α). Conclusions Rather than developing compensatory LVH, pressure overload in CMC NF-κB deficient mice resulted in functional deterioration that was associated with increased fibrosis, decreased HIF expression, and decreased microvessel density. These observations mechanistically implicate NF-κB, and its regulation of hypoxic stress, as an important factor determining the path between adaptive hypertrophy and maladaptive heart failure.

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