| Various stimuli, including a high dietary fat, starvation, pressure overload and administration of certain drugs, have been shown to cause cardiac stress and compromise myocardial function. Among the various factors, chronic intake of HFD has been deemed to be the major contributor to the development of obesity. If uncorrected, obesity promotes the onset and development of cardiac hypertrophy and myocardial dysfunction, contributing to the high cardiac morbidity and mortality in obese individuals. In contrast to nutrition overload, malnutrition or starvation has been shown to cause cardiac geometry and function changes. In addition to the nutrition disturbance, increased pressure overload is another major factor for the development of cardiac hypertrophy and myocardial dysfunction. Initially, it is an adaptive and beneficial process; however, sustained pressure overload triggers its transition to be maladaptive and finally develops to the stage of heart failure. The development of cardiomyopathy, and even heart failure, can also be attributed to the side effects of certain drugs, that are used for the treatment of other diseases. Among these drugs, anticancer agent doxorubicin is extensively studied because of its protective effect against cancer and its high cardiotoxicity. As one of the most powerful anticancer drugs, doxorubicin has been used for more than 80 years. However, accumulating studies have demonstrated the fatal cardiotoxic side effects of doxorubicin treatment.;Autophagy is an evolutionarily conserved cellular pathway involved in degradation and recycling of long-lived intracellular proteins and cytoplasmic organelles. In theory, autophagy can either promote cell survival or cell death. On one hand, autophagy is protective through clearing off the damaged organelles and dysfunctional proteins, or through refreshing the amino acid pool and providing new intracellular energy. However, on the other hand, over-activated autophagy could be detrimental through the excessive degradation of essential cellular constituents. Under physiological conditions, the basal level of autophagy plays an indispensable role in maintaining cardiac geometry and function through degrading intracellular components and supplying intracellular energy. Although autophagy activity is maintained at low-levels in the heart under physiological conditions, it is susceptible for disturbance by a number of cardiovascular diseases including ischemia-reperfusion, pathological hypertrophy, and heart failure. However, the role of autophagy in the heart under different pathological conditions is still controversial.;Thus the objective of my PhD project was to study whether, and how, cardiac autophagy is involved in maintaining cardiac function under different pathological conditions including HFD-induced obesity and type II diabetes, starvation-induced cardiac injury, pressure overload-induced cardiac hypertrophy and doxorubicin-induced cardiomyopathy. Alterations in signaling key molecules involved in autophagy under HFD, starvation, pressure overload and doxorubicin challenge were explored. First, my data indicated that HFD-induced cardiac dysfunction was associated with disruption of the autophagosome maturation process, which could be rescued by Akt2 knockout. Furthermore, my data demonstrated that rescuing defective autophagosome maturation processes is pivotal for the cardioprotective effect of Akt2 knockout against high fat diet-induced obesity. Secondly, we evaluated the role of MIF (macrophage migration inhibitory factor) in HFD-induced obesity and diabetic cardiomyopathy, with a focus on the role of inflammation and autophagy. We observed that MIF deficiency did not prevent HFD-induced obesity and whole-animal energy utilization disturbance. Interestingly, our results showed that MIF deficiency prevented HFD-induced diabetic cardiomyopathy. The cardioprotective effect of MIF deficiency is associated with improved myocardial inflammation and autophagy in HFD-induced diabetic myocardium. Thirdly, we studied if and how MIF is involved in cardiac geometry and function changes during starvation. Our results showed that MIF knockout was able to unmask starvation-induced cardiac injury. Although the underlying mechanisms are complex, our data suggests that MIF plays a permissive role in the maintenance of cardiac geometry and function under starvation by regulation of autophagy. Fourthly, my study showed autophagy activation was beneficial in protecting cardiac hypertrophy exacerbation under pressure overload. More importantly, pressure overload-induced cardiac autophagy activation was shown to be mediated by MIF through activating AMPK and inhibiting mTOR activity. Besides, mitochondrial autophagy (mitophagy) was found to be a dominant form of MIF-mediated autophagy in pressure overload-induced hypertrophic heart. The cardiac toxicity of doxorubicin was shown to be associated with disrupted cardiac autophagic flux activity, the effect of which is exacerbated by MIF knockout. Rescuing autophagy by rapamycin treatment dramatically attenuated doxorubicin-induced cardiac dysfunction and mortality in MIF-/- mice. Taken together, these data provide evidence suggesting that autophagy is beneficial in maintaining cardiac function under pathological stress conditions including HFD-induced obesity and type II diabetes, pressure overload-induced cardiac hypertrophy and doxorubicin-induced heart failure. |
