Novel insights into intimal hyperplasia in cardiac allograft vasculopathy

同种异体心脏移植血管病变中内膜增生的新认识 外科和经皮介入治疗方面的生物技术进步极大地改善了心血管疾病 治疗。然而，血管平滑肌细胞(SMC)不受控制的增殖和再狭窄 移行导致闭合性内膜增生，仍然是一个尚未解决的主要障碍。SMC拥有独特的 能够改变其表型以响应环境刺激，从而允许血管愈合和生长。 然而，这种SMC的可塑性也会导致心血管疾病，包括内膜增生。 在血管重建术之后。一种特别耐受且致命的内膜增生症发生在 干扰素γ介导的慢性免疫损伤促进弥漫性和多发性心脏移植血管病变 严重的SMC内膜增生遍及移植器官的所有血管，导致缺血性器官衰竭。 迫切需要更好地了解这种SMC反应，以确定潜在的治疗靶点 卡夫。MTORC1抑制剂已显示出治疗CAV的前景，但受到不良反应的限制。通过理解 MTORC1下游的分子靶点，我们或许能够概括抑制mTORC1的好处 在防止全身并发症的同时，还可以减少SMC的风险。 最近发现的一些SMC病变的克隆起源，包括在动脉粥样硬化中，已经发生了转变。 我们如何看待血管疾病的范例。的确，这种导致克隆性损伤的“先锋”细胞可能 参与CAV新生内膜的早期发病机制。此外，表观遗传学可能在这方面发挥重要作用。 过程，但我们对表观遗传学如何影响CAV的了解有限。我们最近确定了TET2 作为mTORC1抑制剂雷帕霉素诱导的SMC表型的主要表观遗传调节因子。TET2 在损伤后的内膜增生和动脉粥样硬化病变中被抑制(循环2013)。我们现在 证实TET2在人血管内皮细胞、小鼠同种异体移植模型和干扰素γ中的表达下调。 培养的SMC。在缺乏在整个冠状动脉血管系统中过表达TET2的治疗方法的情况下， 我们认为抑制TET2表达的miRNAs，如miR29等，可以作为CAV的靶点 心理治疗。为了确定新的机制和治疗靶点，我们建立了一种小鼠异位心脏 CAV移植模型的建立。我们假设表观遗传(染色质和miRNAs)和转录 改变SMC基因表达，促进冠状动脉内膜增生 移植的心脏。利用生物技术的进步，我们开发了一种协调、互补、 非重叠三管齐下的方法，以加深我们对该病的理解和开发新的治疗方法 CAV包括：1)克隆性和起始事件，2)表观基因组学和转录组学，以及3)基于miRNA 治疗。我们招募了一支杰出的国际公认的外科医生团队-科学家、病理学家、 血管生物学家、表观遗传学/生物信息学和miRNA专家，以解决这些目标。

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 IFNγ 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 IFNγ 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.