Cyclic intermittent hypoxia (IH) is emerging as an important factor in the development of insulin resistance and cardiovascular diseases in patients with obstructive sleep apnea (OSA). OSA is very common in congestive heart failure (CHF) occurring in up to a third of patients. Insulin resistance has also been linked to the development of cardiac dysfunction. Treatment of OSA with continuous positive airway pressure (CPAP) alleviates the IH during sleep, increases insulin sensitivity, as well as improves cardiac function, suggesting that IH is a crucial factor affecting myocardial function. The mechanisms by which IH is responsible for insulin resistance and associated cardiovascular diseases and myocardial dysfunctions are unclear. Adipose tissue synthesizes and secretes a wide variety of bioactive peptides which are collectively called "adipocytokines". Adiponectin (Ad), an adipoctyokine that is exclusively synthesized in white adipose tissue, has received considerable attention in recent years because of its potent physiological effects and pleiotropic actions which include its antidiabetic, antiatherogenic, and anti-inflammatory effects. Total circulating Ad levels have been shown to be lower in insulin-resistant individuals. Whether cyclic IH (similar to that encountered during the IH associated with OSA in humans) decreases Ad expression and secretion in adipocytes is not known. Therefore, in Specific Aim 1, we will examine whether IH alters Ad secretion in adipocytes resulting in increased insulin resistance in these cells. Ad protects against the development of systolic dysfunction following myocardial infarction. Ad deficiency leads to progressive cardiac remodeling in pressure overloaded condition and it also prevents cellular hypertrophy in cultured myocytes. It is not known whether the insulin resistance induced by IH contributes to myocardial dysfunction. Therefore, in Specific Aim 2, we will establish that adiponectin plays an important role in the modulation of insulin resistance and associated myocardial dysfunction induced by intermittent hypoxia in vivo, in animal models. Since insulin resistance is a risk factor for left ventricular systolic and diastolic function, and also our preliminary data show that treatment of IH in OSA increases the biologically active high-molecular-weight form of Ad, Specific Aim 3 of this proposal will involve translational research to examine the effects of CPAP treatment in human patients with OSA and heart failure, on insulin resistance and Ad levels, and associate these with changes in cardiac structure and function using cardiac magnetic resonance imaging. To carry out this proposal, we have assembled a team consisting of clinicians, basic scientist, and a leading authority on Ad biology. These collaborative efforts among clinician scientists and basic scientists, in a supportive environment at the Dorothy M. Davis Heart &Lung Institute of the Ohio State University College of Medicine, allow us to perform these experiments from cells and animal models to human subjects.
Intermittent hypoxia associated with obstructive sleep apnea is a very common problem that is an important risk factor for cardiovascular disease. Knowledge of the mechanisms of how adiponectin protects against intermittent hypoxia-induced insulin resistance and associated myocardial dysfunction, may provide novel treatment strategies for patients with sleep apnea and cardiovascular disease.
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