Results from our and other laboratories demonstrate that a critical amount of ROS and a redox state within a certain boundary is critical for coronary collateral growth;however, oxidative stress, i.e., a shift in the redox state to a more oxidative environment, impairs coronary collateral growth. Previous investigations fall short of ascertaining the cell type (or types), in which alterations of redox state matter, and where redox signaling is critical. The overarching goal of this proposal is to determine the cell type or types in the heart responsible for redox signaling in the growth of the coronary collateral circulation in response to repetitive ischemia. A corollary to this aim is that we will also determine the cell type or types in which oxidative stress confers negative influences on coronary collateral growth. To solve these problems we propose the following specific aims:
Aim 1. Determine in which cell type (or types) does oxidative stress corrupt coronary collateral growth. We will induce oxidative stress in the coronary endothelium, smooth muscle cells and cardiac myocytes using the cell-specific promoters VE-Cadherin, SM22, and cardiac myosin heavy chain (CMHC), respectively. Cells will be transfected with a plasmid (using in vivo electroporation) or transduced with an adenovirus expressing an iNOS mutant (E371A) that does not bind arginine, and therefore, only produces O2.
Aim 2. Determine in which cell type (or types) the redox sensitive p38 MAPK is critical for coronary collateral growth. We will transfect or transduce coronary endothelium, smooth muscle cells and cardiac myocytes using cell-specific promoters described for Aim 1 using a vector expressing a dominant/negative p38 MAPK (DNp38). After determining the particular cell type in the heart most sensitive to the effects of oxidative stress and redox signaling in coronary collateral growth, we will extend our findings to an animal model of vascular pathology (the JCR rat: a model of the metabolic syndrome), which demonstrates poor coronary collateral growth. Specifically in the final two aims we will:
Aim 3. Determine the cell type where reducing oxidative stress by over expressing Nrf2 in the JCR rat (a model of reduced coronary collateral growth and oxidative stress) will restore collateral growth.
Aim 4. Determine the cell type where expression of a constitutively active p38 MAP kinase will restore collateral growth in the JCR rat. The proposed studies employ a multifaceted approach to solving cell-specific signaling in vivo by employing techniques to determine cell specific changes in protein expression, thiol oxidation and ROS production and ultimately linking these measurements to coronary collateral growth. These studies will provide insight into the cell-specific locations where ROS and redox signaling modulate coronary collateral growth.
Ischemic heart disease (IHD) continues to be one of the leading causes of death in the United States, and represents a major cost in the US healthcare system. The presence of a well developed collateral circulation in the heart has a tremendous impact on the morbidity and mortality of IHD. Patients with well developed collaterals show a lower incidence of sudden death, have smaller infarcts in the event of an occlusion, and demonstrate a better prognosis than patients with poor collaterals (low conductance or evidence of collateral growth). It is also worth noting that about 40% of patients with IHD demonstrate very little to no coronary collaterals. It is also recognized that many risk factors for IHD, e.g., hypertension, obesity, dyslipidemia, which also produce oxidative stress, have a negative influence on coronary collateral growth. However, the cell type where the corruption occurs, e.g., does oxidative stress corrupt the production of growth factors by cardiac myocytes, or does it corrupt endothelial responsiveness to growth factors, remains unknown. The goal of this proposal is to delineate the cell type in the heart where redox signaling and oxidative stress matter for coronary collateral growth. The ultimate goal of this project is to provide the foundation for more directed therapies to stimulate the growth of coronary collaterals in patients with IHD.
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