Diabetic patients suffer from several cardiovascular complications that include hyperlipidemia, atherosclerosis, increased risk for myocardial infarction (MI) and declined global cardiac function. It is also recognized that diabetics have deficits in wound healing in key tissues throughout the body. In the heart, diabetes induces myocardial fibrosis leading to impaired contractile function and eventually, heart failure. Diabetic patients are also well known to have reduced survival rates following myocardial infarction (MI), the mechanisms that underlie this are not clear. The myocardium adapts to ischemia-induced infarction by activating specific cellular responses to this injury. Cardiac fibroblasts (CFs) and myofibroblasts are the critical mediators of myocardial repair, and are acutely active following MI to stabilize the infarcted area and limit the extent of the ischemic injury. Determining the mechanisms that cause limitations in diabetic wound healing, increased fibrosis, and poor recovery from MI are the overall goals of this proposal. Significant focus will be given to myofibroblasts, the hypersecretory fibroblastic phenotype that is essential for proper wound healing following acute injury. We have recently determined in a type 1 diabetic rat model that the diabetic myocardium contains significantly reduced numbers of cardiac myofibroblasts in the basal (uninjured) state, leading us to hypothesize that this reduction in myofibroblasts decreases the wound healing ability of the myocardium in response to MI.
Our specific aims for this proposal are 1) to determine the effects of elevated glucose (and insulin resistance) on cardiac myofibroblast differentiation 2) to determine whether and to what extent the myofibroblast content contributes to deficits n post-infarction remodeling and function in the diabetic heart and 3) to determine whether direct injection of myofibroblasts in the ischemic zone of the infarcted diabetic myocardium will accelerate post-MI wound healing leading to improved cardiac function. These studies could identify new therapeutic targets and open new avenues for treatment of diabetic cardiomyopathy.
Diabetic patients suffer from cardiovascular complications that include high cholesterol, atherosclerosis, and increased risk of death following a heart attack (or myocardial infarction;MI), although the underlying causes of these complications, particularly the increased mortality post-MI, are not well defined. We believe that the high mortality rate may be directly related to a deficit in myofibroblasts, which are specialized wound healing cells that are critical for wound healing and repair in nearly every major organ in the body. This proposal aims to understand the basic mechanisms that underlie the poor post-MI recovery during diabetes and identify potential new avenues for the prevention and treatment of this disease.
|Adapala, R K; Thoppil, R J; Ghosh, K et al. (2016) Activation of mechanosensitive ion channel TRPV4 normalizes tumor vasculature and improves cancer therapy. Oncogene 35:314-22|
|Thodeti, Charles K (2015) A bouquet for a broken heart: can flowers repair a damaged heart? Circ Res 116:1729-31|
|Shamhart, Patricia E; Luther, Daniel J; Adapala, Ravi K et al. (2014) Hyperglycemia enhances function and differentiation of adult rat cardiac fibroblasts. Can J Physiol Pharmacol 92:598-604|
|Adapala, Ravi K; Thoppil, Roslin J; Luther, Daniel J et al. (2013) TRPV4 channels mediate cardiac fibroblast differentiation by integrating mechanical and soluble signals. J Mol Cell Cardiol 54:45-52|
|Thodeti, Charles K; Paruchuri, Sailaja; Meszaros, J Gary (2013) A TRP to cardiac fibroblast differentiation. Channels (Austin) 7:211-4|
|Luther, Daniel J; Thodeti, Charles K; Shamhart, Patricia E et al. (2012) Absence of type VI collagen paradoxically improves cardiac function, structure, and remodeling after myocardial infarction. Circ Res 110:851-6|