Novel insights into intimal hyperplasia in cardiac allograft vasculopathy Biotechnical advances in surgical and percutaneous interventions have greatly improved cardiovascular disease therapies. However, restenosis arising from uncontrolled vascular smooth muscle cell (SMC) proliferation and migration leading to occlusive intimal hyperplasia, remains a major unresolved hurdle. SMC possess a unique ability to alter their phenotype in response to environmental stimuli, which allows for vascular healing and growth. However, this SMC plasticity also contributes to cardiovascular pathologies, including intimal hyperplasia following revascularization procedures. A particularly resistant and deadly form of intimal hyperplasia occurs in cardiac allograft vasculopathy (CAV) where chronic immune injury mediated by IFN? promotes diffuse, and often severe, SMC intimal hyperplasia throughout the vessels of the grafted organ, leading to ischemic organ failure. A better understanding of this SMC response is urgently warranted to identify potential targets for therapy for CAV. mTORC1 inhibitors have shown promise for CAV but are limited by adverse effects. By understanding the molecular targets downstream of mTORC1, we may be able to recapitulate the benefits of mTORC1 inhibition in SMC while preventing systemic complications. The recent discovery of the clonal origin of some SMC lesions, including in atherosclerosis, has shifted paradigms in how we view vascular disease. Indeed, such ?pioneering? cells that give rise to clonal lesions may be involved in the early pathogenesis of neointima in CAV. Moreover, epigenetics may play a major role in this process, but we have limited understanding of how epigenetics influence CAV. We have recently identified TET2 as a master epigenetic regulator of SMC phenotype that is induced by the mTORC1 inhibitor rapamycin. TET2 is repressed in intimal hyperplasia post-injury and in atherosclerotic lesions (Circulation 2013). We now demonstrate that TET2 is downregulated in SMC in human CAV, in mouse allograft models, and by IFN? in cultured SMC. In the absence of a therapeutic method to overexpress TET2 throughout the coronary vasculature, we propose that miRNAs that repress TET2 expression, such as miR29 and others, could be targeted for CAV therapy. To identify novel mechanisms and therapeutic targets, we have established a mouse heterotopic heart transplant model of CAV. We hypothesize that epigenetic (chromatin and miRNAs) and transcriptional changes alter SMC gene expression, promoting intimal hyperplasia in the coronary arteries of transplanted hearts. Using biotechnological advances, we have developed a coordinated, complementary, non-overlapping 3-pronged approach toward furthering our understanding of and developing new treatments for CAV that includes: 1) clonality and initiating events, 2) epigenomics and transcriptomics, and 3) miRNA-based therapies. We have recruited an outstanding internationally recognized team of surgeon-scientists, pathologists, vascular biologists, epigenetics/bioinformatics and miRNA experts to address these goals.
Organ transplants are a lifesaving surgical procedure for chronic heart, lung, or kidney disease. The major cause of transplant failure is allograft vasculopathy, a form of chronic rejection in which immune injury prompts smooth muscle cells to proliferate excessively and occlude the blood vessels of the transplanted organ, leading to organ failure due to insufficient blood flow. We propose new studies to understand the origin of this inappropriate smooth muscle response, and will test new therapies to prevent it.
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