Relevant Degree Programs
Graduate Student Supervision
Doctoral Student Supervision (Jan 2008 - Mar 2019)
Introduction: Cardiac hypertrophy is an adaptive response to increased myocardial workload that becomes maladaptive when hypertrophied hearts are exposed to an acute metabolic stress, such as ischemia/reperfusion. Acceleration of glycolysis occurs as part of the hypertrophic response and may be maladaptive because it enhances glycolytic metabolite accumulation and proton production. Activation of AMP-activated protein kinase (AMPK), a kinase involved in the regulation of energy metabolism, is proposed as a mechanism for the acceleration of glycolysis in hypertrophied hearts. However, this concept has not yet been proven conclusively. Additionally, several studies suggest that AMPK is involved in hypertrophic remodeling of the heart by influencing cardiac myocyte growth, a suggestion that remains controversial.Hypothesis: AMPK mediates hypertrophic remodeling in response to pressure overload. Specifically, AMPK activation is a cellular signal responsible for accelerated rates of glycolysis in hypertrophied hearts. Additionally, AMPK influences myocardial structural remodeling and gene expression by limiting hypertrophic growth.Experimental Approach: To test this hypothesis, H9c2 cells, derived from embryonic rat hearts, were treated with (1 µM) arginine vasopressin (AVP) to induce hypertrophy. Substrate utilization was measured and the effects of AMPK inhibition by either Compound C or by adenovirus-mediated transfer of dominant negative AMPK were determined. Subsequently, adenovirus-mediated transfer of constitutively active form of AMPK (CA-AMPK) was expressed in H9c2 to specifically increase AMPK activity and, thereby, further characterize the role of AMPK in hypertrophic remodeling.Results: AVP induced a metabolic profile in hypertrophied H9c2 cells similar to that in intact hypertrophied hearts. Glycolysis was accelerated and palmitate oxidation was reduced with no significant alteration in glucose oxidation. These changes were associated with AMPK activation, and inhibition of AMPK ameliorated but did not normalize the hypertrophy-associated increase in glycolysis. CA-AMPK stimulated both glycolysis and fatty acid oxidation, and also increased protein synthesis and content. Howver, CA-AMPK did not induce a pathological hypertrophic phenotype as assessed by atrial natriuretic peptide expression.Conclusion: Acceleration of glycolysis in AVP-treated hypertrophied heart muscle cells is partially dependent on AMPK. AMPK is a positive regulator of cell growth in these cells, but does not induce pathological hypertrophy when acting alone.
Master's Student Supervision (2010-2017)
The existence of a heart muscle disorder specific to Diabetes Mellitus (DM) has been proposed, termed, Diabetic Cardiomyopathy (DCM). DCM is defined as the presence of an early asymptomatic diastolic dysfunction that eventually progresses to overt systolic dysfunction in the absence of ischemic or valvular heart disease. Metabolic impairment and increased oxidative stress have been highlighted as causes. The β-blocker metoprolol is known to improve function in diabetic rat hearts, possibly through amelioration of the sequelae associated with oxidative stress, without lowering oxidative stress. It is unclear if lowering oxidative stress in concert with metoprolol treatment would improve function further. Ascorbic Acid (AA) is a potent antioxidant and has been shown to improve function in the diabetic rat heart. Hypothesis:We propose that metabolic changes that occur during diabetes elevate oxidative stress, leading to protein damage, signaling changes, cell death and other sequelea; the eventual sum of these changes is an impairment of function. Treatment of either the sequelae of oxidative stress or oxidative stress directly will be beneficial but treatment of both will improve function further. To accomplish our study we induced DM in male Wistar rats using 60 mg/kg streptozotocin and treated them with metoprolol at 15 mg/kg/day via osmotic pump and/or AA at 1000 mg/kg/day via drinking water. In order to study the effect of treatment on the development of dysfunction we studied a time point before and after development of dysfunction (5 and 7 weeks, respectively). Blood was collected to assess the severity of diabetes and echocardiography performed to assess in vivo heart function. At termination, ex vivo heart function and substrate use were measured by working heart perfusion. Tissue was collected for measurements of metabolite levels and oxidative protein damage. Function significantly worsened in association with metabolism and oxidative damage. Both drugs improved function, while only AA reduced oxidative damage. Combined treatment led to improvement in function more pronounced then single treatment. Our β-blocker and antioxidant treatment strategy focuses on oxidative stress, and not on diabetes specifically, thus it may prove useful in other disease where oxidative stress contributes to pathology.