News & Research

    Thomas Jefferson University, Philadelphia, Pennsylvania

Adiponectin Resistance in Diabetic Heart and Its Underlying Molecular Mechanisms

General Research Subject: Type 2 Diabetes

Focus: Signal Transduction (Non-Insulin Action)\Cytokines and Apoptosis, Signal Transduction (Non-Insulin Action)\Hormones

Type of Grant: Basic Science

Project Start Date: July 1, 2011

Project End Date: June 30, 2014

Research Description

Ischemic heart disease (IHD) remains the number 1 killer in our country and diabetes is the major cause leading to IHD. However, specific mechanism underlying why diabetes is so prone to IHD is unknown. Adiponectin (APN) is a protein made primarily by fat cells (adipocytes), and has cardioprotective properties.  However, how this fat cell-derived protein protects heart remains largely unknown. We have recent demonstrated that the cardioprotective effects of APN critically depend on the protein caveolin 3 (Cav3, the structural protein for caveolae which are flask-shaped plasma membrane invaginations). Additional preliminary experimental results suggested that direct interaction of Cav3 with a cell surface protein that specifically binds with APN (APN receptor, AdipoR1) is required for APN biological function, and that these two protein interaction is disrupted in diabetic heart due to Cav3 modification by reactive nitrogen species. These uniquely new results led to our novel hypothesis that nitrative dissociation of Cav3/AdipoR1 causes heart irresponsible to APN (APN resistance) and contributes  to diabetic cardiac injury. Two 2 specific aims will be addressed. Specific aim 1 will reveal the molecular mechanisms by which Cav3 nitration causes dissociation of Cav3/AdipoR1. Completion of this aim will identify a novel molecular mechanism contributing to APN resistance and cardiac injury in the diabetic heart. Specific aim 2 will identify potential therapeutic strategies to restore Cav3/AdipoR1 interaction, enhancing APN cardioprotective action in the diabetic heart. Completion of this aim will identify novel targets harboring therapeutic potential against myocardial ischemia/reperfusion (MI/R) injury in diabetic patients.

Research Profile

What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?

We have recently demonstrated that caveolin 3 (Cav3)/AdipoR1 interaction is an essential element in APN transmembrane signaling, and that nitrative modification of Cav3 in the diabetic heart causes their dissociation. To obtain direct evidence supporting a novel hypothesis that nitrative dissociation of Cav3/AdipoR1 causes cardiac APN resistance and contributes to diabetic cardiac injury, the following 2 specific aims will be addressed. Specific aim 1 will reveal the molecular mechanisms by which Cav3 nitration causes dissociation of Cav3/AdipoR1. Completion of this aim will uncover the molecular mechanisms responsible for nitrative disruption of Cav3/AdipoR1 interaction, and identify a novel molecular mechanism contributing to APN resistance and cardiac injury in the diabetic heart. Specific aim 2 will identify potential therapeutic strategies to restore Cav3/AdipoR1 interaction, enhancing APN cardioprotective action in the diabetic heart. Completion of this aim will not only prove our concept using an in vivo model, but also identify novel targets harboring therapeutic potential against myocardial ischemia/reperfusion (MI/R) injury in diabetic patients.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?

Ischemic heart disease (IHD) remains the number 1 killer in our country and diabetes is the major cause leading to IHD. However, specific mechanism underlying why diabetes is so prone to IHD is unknown. Adiponectin (APN) is a protein made primarily by fat cells (adipocytes), and has cardioprotective properties.  However, how this fat cell-derived protein protects heart remains largely unknown. We have recent demonstrated that the cardioprotective effects of APN critically depend on the protein caveolin 3 (Cav3, the structural protein for caveolae which are flask-shaped plasma membrane invaginations). Additional preliminary experimental results suggested that direct interaction of Cav3 with a cell surface protein that specifically binds with APN (APN receptor, AdipoR1) is required for APN biological function, and that these two protein interaction is disrupted in diabetic heart due to Cav3 modification by reactive nitrogen species. These uniquely new results led to our novel hypothesis that nitrative dissociation of Cav3/AdipoR1 causes heart irresponsible to APN (APN resistance) and contributes to diabetic cardiac injury. If we can define clearly the molecular mechanisms and machinery responsible for Cav3 mediated anti-oxidative/anti-nitrative signaling of APN, we might be able to identify entirely new therapeutic targets for diabetic individuals suffering ischemic heart disease, with the ultimate goal of preventing and/or attenuating ischemic cardiac injury.

Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?

My research interests have focused on the molecular and cellular mechanisms of ischemic heart disease since 1979. Accumulating evidence now indicating that an ischemic heart disease is the major cause of morbidity and mortality in patients with diabetes mellitus. On the other hand, type 2 diabetes has been shown to be the major risk factor for ischemic diseases. Therefore, I strongly believe that identifying signaling mechanisms that lead to vascular injury in diabetes, thus enabling the prevention of the development of IHD in diabetic patients (reducing morbidity of IHD in diabetic patients) and that identifying the mechanisms that render diabetic hearts to be more susceptible to ischemic/reperfusion injury, thus enabling identification of novel therapeutic targets that will improve the final outcome of diabetic patients with IHD (reducing mortality of IHD in diabetic patients) are both scientifically and practically important. This award will enable me to focus on a novel proposal that I have already started. Specifically, with this support, I wish to obtain solid evidence to support my central hypothesis that nitrative dissociation of Cav3/AdipoR1 causes cardiac APN resistance and contributes to diabetic cardiac injury.

In what direction do you see the future of diabetes research going?

I feel strongly that translational research will be the future direction for diabetic research. Specifically, we need to combine molecular biology, cellular biology, in vivo experimental animal studies and clinical studies together to identify clinically applicable targets that will reduce the morbidity and mortality of diabetes and its cardiovascular complications.