The Regulation of Cardiac Nrf2 During an Acute Glucose Challenge and the Impact on Mitochondrial Function During Insulin Resistance and Type II Diabetes Mellitus
During the progression of Type II diabetes hearts are under stress due to increases in oxidant production and contractile force from elevated blood pressure. Pre-diabetic and diabetic individuals undergo periods of hyperglycemia which contribute significantly to oxidant production while elevated blood pressure also contributes to the influx of oxidant production. The renin angiotensin system is responsible for blood pressure homeostasis and becomes chronically elevated during metabolic derangements. Furthermore, chronic low-grade inflammation mediated through NF-κB is present during the disease manifestation which has been reported to be antagonistic of Nrf2, a transcription factor with a wide array of cellular detoxifying genes. The objectives of these projects were to elucidate the impact a hyperglycemic event has on insulin resistant and diabetic hearts, the role of AT1 activation of mitochondrial function and antioxidant capacity, and the changes in NF-kB and Nrf2 signaling as type II diabetes progresses. In the first chapter we demonstrate that insulin resistant hearts experience mitochondrial dysfunction and increases in damage, while blocking the AT1 receptor increases Nrf2 binding to the electrophile response element during an acute glucose challenge. In the second chapter we demonstrate that diabetic hearts increase glutathione content in response to glucose and that antagonism of the AT1 receptor has beneficial impacts on Nrf2 related gene expression. We also demonstrate that non-diabetic animals increase Nrf2 related genes after a glucose bolus indicating that Nrf2 increases in response to glucose. The third chapter examines the relationship between cardiac Nrf2 and NF-κB during the progression of diabetes. Here we demonstrate that nuclear NF-κB content and acetylation increases rapidly as type II diabetes progresses and that nuclear Nrf2 content and acetylation is blunted. This is the first time that acute glucose challenges have been performed in in vivo during both insulin resistant and type II diabetic animals where blockade of the AT1 has been incorporated. Our findings contribute to the understanding of antioxidant defense during hyperglycemic events through the progression of type II diabetes. These studies illustrate the importance of antioxidant defense during even the early stages of insulin resistance and bolster the idea that antioxidant defense is impaired during hyperglycemic events.