Abstract
Patients with insulin resistance and type 2 diabetes have poor cardiac outcomes following myocardial infarction (MI). The mitochondrial uncoupling protein 3 (UCP3) is down-regulated in the heart with insulin resistance. We hypothesized that decreased UCP3 levels contribute to poor cardiac recovery following ischemia/reperfusion (I/R). After confirming that myocardial UCP3 levels were systematically decreased by 20–49% in animal models of insulin resistance and type 2 diabetes, we genetically engineered Sprague–Dawley rats with partial loss of UCP3 (ucp3+/−). Wild-type littermates (ucp3+/+) were used as controls. Isolated working hearts from ucp3+/− rats were characterized by impaired recovery of cardiac power and decreased long-chain fatty acid (LCFA) oxidation following I/R. Mitochondria isolated from ucp3+/− hearts subjected to I/R in vivo displayed increased reactive oxygen species (ROS) generation and decreased respiratory complex I activity. Supplying ucp3+/− cardiac mitochondria with the medium-chain fatty acid (MCFA) octanoate slowed electron transport through the respiratory chain and reduced ROS generation. This was accompanied by improvement of cardiac LCFA oxidation and recovery of contractile function post ischemia. In conclusion, we demonstrated that normal cardiac UCP3 levels are essential to recovery of LCFA oxidation, mitochondrial respiratory capacity, and contractile function following I/R. These results reveal a potential mechanism for the poor prognosis of type 2 diabetic patients following MI and expose MCFA supplementation as a feasible metabolic intervention to improve recovery of these patients at reperfusion.
Highlights
In the United States alone, more than 35 million individuals are suffering from diabetes mellitus
An even stronger decrease in cardiac uncoupling protein 3 (UCP3) content was observed in the LoxTB melanocortin 4 receptor (MC4R)−/− mice (28–34% decrease) and LepR/Nestin-cre mice (38–40% decrease; Fig. 1e, g), two other models of type 2 diabetes which are characterized by severe obesity, insulin resistance, hyperinsulinemia, and glucose intolerance [7, 49]
A strong 36–49% decrease in cardiac UCP3 content was observed in the MC4R knockout rats (MC4RKO) rat (Fig. 1f, g), a rodent model with marked obesity, insulin resistance, and hyperinsulinemia [65]
Summary
In the United States alone, more than 35 million individuals are suffering from diabetes mellitus. By 2030, this diabetes epidemic is expected to extend to more than 54 million Americans and will lead to nearly 400,000 deaths annually [57]. Cardiovascular disease is the most prevalent cause of mortality in diabetic patients [43]. Type 2 diabetes mellitus represents > 95% of all diabetes cases [24]. Diabetic individuals represent a rapidly growing number of the patients undergoing reperfusion for acute myocardial infarction [63]. In addition to increasing the incidence of myocardial infarction (MI), diabetes is associated with increased cardiac morbidity and mortality following revascularization [15, 19, 66]. While the pathophysiology of cardiovascular diseases in diabetes is complex
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