Wang, Yajing , M.D., Ph.D.
Caveolin-3 as a novel therapeutic target in diabetic cardiomyocyte injury
General Research Subject: Type 2 Diabetes
Focus: Complications\Macrovascular-Cellular Mechanisms of Atherogenesis in Diabetes, Signal Transduction (Non-Insulin Action)\Cytokines and Apoptosis, Signal Transduction (Non-Insulin Action)\Hormones
Type of Grant: Junior Faculty
Project Start Date: January 1, 2011
Project End Date: December 31, 2013
Diabetes Type: Type 2 diabetes
An overwhelming population of diabetic patients suffer great complications (morbidity) and death (mortality) from ischemic heart disease (IHD). The 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 APN receptor 1 (AdipoR1)/Cav3 interaction positively regulates APN transmembrane signaling and that this novel protein/protein interaction is impaired in diabetic heart. These uniquely new results led to our novel hypothesis that there exists a AdipoR1/Cav3/AC/cAMP/PKA signaling axis that protects ischemic/reperfused hearts by inhibiting NFƒÛB-mediated NADPH oxidase overexpression and resultant oxidative/nitrative stress. The experiments outlined in this grant application will combine traditional pharmacological and modern gene manipulation approaches to determine how the AdipoR1/Cav3 interaction mediates APN's anti-oxidant/anti-nitrative signaling (Aim 1), and whether therapeutic interventions promoting AdipoR1/Cav3 signaling may restore diminished APN-provided cardioprotection in advanced-obesity animals (Aim 2). The novel data gleaned from this application's proposed studies will be scientifically significant, because it will contributive to defining how APN specifically exerts its cardioprotective effects. This application will also be clinically significant because defining caveolin-mediated anti-oxidative/anti-nitrative signaling mechanisms may reveal entirely new therapy modalities for the successful treatment of diabetic patients with ischemic heart disease.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Ischemic heart disease (IHD) is the major cause of morbidity and mortality in diabetic patients. However, the molecular basis linking diabetes to cardiovascular complications has not yet been fully defined. Adiponectin (APN), a protein abundantly made by adipocytes, regulates metabolism, and is both vasculo- and cardiac-protective. Plasma levels of APN are significantly reduced in type II diabetes and inversely related to the risk of IHD, indicating that reduced APN may play a critical role in the development of IHD in diabetic patients. We and others have demonstrated that myocardial ischemia/reperfusion (MI/R) induced oxidative/nitrative stress and cardiac injury is extremely exaggerated in mice lacking APN, further suggesting that reduced APN levels have negative impact on the progression of cardiomyocyte death after diabetic patients develop IHD. Therefore, defining APN's cytoprotective signaling mechanisms may potentially identify novel cardioprotective targets for the prevention and treatment of diabetic ischemic heart disease.
Our most recent study demonstrated that the anti-oxidative/anti-nitrative and cardioprotective effects of APN were critically dependent upon caveolin 3 (Cav3). Additional experimental results further demonstrated that APN receptor 1 (AdipoR1) co-localizes and directly interacts with Cav3, and that the formation of AdipoR1/Cav3 complex was inhibited when cardiomyocytes were cultured in high glucose/high lipid medium. These novel findings suggest that signaling pathway(s) mediated by this novel protein/protein interaction (AdipoR1/Cav3) may play a critical role in APN's anti-oxidant cardioprotective actions of particular consequence in the diabetic heart.
By defining carefully the molecular mechanisms responsible for Cav3 mediated anti-oxidative/anti-nitrative signaling of APN, we hope to identify novel cardioprotective targets for diabetic individuals with an impaired APN-caveolin signaling axis, and therefore prevent and/or ameliorate ischemic cardiac injury.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Diabetic patients are prone to ischemic heart disease (IHD), which constitutes an overwhelming cause of disability and death in this patient population. The specific molecular reasons underlying why diabetics are at particular risk for IHD remain a mystery. Adiponectin (APN) is a protein made by fat cells regulative of metabolism, and has been shown to protect both the blood vessels and the heart. Type II diabetics have reduced levels of this protein in their blood. We and other researchers have clearly shown that animals lacking APN subjected to heart attacks in the laboratory setting (myocardial ischemia/reperfusion MI/R injury) suffer exaggerated injury compared to animals with intact APN. Recently, we have discovered a novel molecular interaction between the protein caveolin 3 (Cav3) and the APN receptor protein AdipoR1, and have shown that their interaction is critical for the protective actions of APN. Furthermore, we have demonstrated in preliminary studies that in diabetic-like conditions, this interaction between Cav3 and AdipoR1 is disrupted, with consequences of impaired APN functioning.
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?
Since my joining Dr Xin-Liang Ma's laboratory at Thomas Jefferson University in Philadelphia in 2007, our focus has centered upon cardiovascular ischemia/reperfusion injury. Simple statistics reveal the devastating influence of diabetes in the United States (~24 million, or nearly 8%, in 2007 per the NIDDK). As a translational medicine researcher, I am acutely focused upon how my basic bench science research has relevant clinical application, with the hopes that my work will one day make influential clinical difference for someone in acute medical crisis and need. With such a large population in need, it is easy to understand the impetus for my daily work.
As I am the child of a mother and father stricken with poorly controlled diabetes and sequelae, there is great personal stake in the race to understand this debilitating disease, one I optimistically hope my own infant son will only learn about as a historical disease. It is my charge and mission to contribute as much as I can to making this aggressive goal a reality.
With the award of this grant, I will not only gain the opportunity to define the roots of diabetic pathology, but shed light on potential therapeutics, the ultimate goal of translational scientific research. Moreover, this award will greatly help me to gain independence.
In what direction do you see the future of diabetes research going?
Many fields of science will influence the course of diabetes research. Solid epidemiology is necessary to provide raw data about the population from which other researchers can draw fresh ideas about diabetic attributes. Trends about the population are similarly as important, to inform us how we are doing by way of treatment, and disease progression in the general populous. As scientific techniques and information base increasingly becomes more sophisticated, fostering of collaboration among diverse scientists and disciplines will become requisite. Novel discovery of molecular mechanisms and exciting therapeutics will require better communication, collaboration, and sharing of data and ideas. Educators and nutritionists will be at the forefront for the maintenance of public health via emphasis of proper diet and daily exercise.
From the basic science laboratory perspective, we must continue to understand the molecular basis for deranged metabolism involved with diabetes. Identification of aberrant signaling or toxic modification of proteins involved in normal physiologic processes is paramount. Combining the traditional biochemical and molecular approaches to research with those aimed at lifestyle and behavior will advance our treatment modalities and success. Translational research approaches must thrive and proliferate, as the divide between bench science and clinical medicine must narrow.
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