Mechanisms and Consequences of Calcification in Aortic Valvular Stenosis

在目前的资助期间，研究重点是氧化应激对心血管的影响。 研究人员观察了“Reversa”主动脉瓣中的氧化应激（ldl“7apoB”/Mtp“"/Mx 1- Cre**）小鼠，发现1/3的小鼠发生中度重度钙化性主动脉瓣狭窄 （CAVS）。研究人员现在提出要检验以下假设：1）局部和体液机制 与氧化应激和炎症相关的因素有助于CAVS的发展，以及2）机制 减少氧化应激和炎症抑制CAVS的发展和进展。 减缓CAVS进展的医学干预将具有重要价值。投资者已经 用已发表的和初步的数据证明，两种方法可以抑制细胞中的信号传导。 成骨通路，减少主动脉瓣钙化。药物干预和 互补的遗传改变的小鼠将用于检查可能导致CAVS的机制。 研究人员将测量小鼠主动脉瓣的基因表达和瓣膜的功能。 目的之一是确定骨保护素（OPG），一种内源性受体诱饵受体， NF κ B配体激活剂（RANKL），降低成骨基因的表达，减少钙化， 瓣膜，并减缓中度主动脉瓣狭窄小鼠的主动脉瓣狭窄进展。学习也 提出测试OPG缺乏（OPG小鼠）加速CAVS的假设。 第二个目标是确定两个相互作用的内源性系统，肾素-血管紧张素和 PPARy，调节CAVS的发展。一种假设是ATI受体有助于发育， CAVS。计划进行研究以确定ATI受体拮抗剂（但不是血管紧张素- 转化酶抑制剂）降低成骨基因的表达并抑制CAVS的发展 在Reversa小鼠中。还计划进行研究，以检验以下假设： ATlr“”小鼠。最后，计划进行研究以检验吡格列酮（一种PPARy配体） 在Reversa小鼠和内皮靶向显性阴性PPARy小鼠中， （E-V290 M），对CAVS的易感性增加。 本课题的目的是利用实验性CAVS模型， 狭窄，以阐明CAVS的分子机制，钙化的功能后果，并探索 可能的治疗方法。 相关性（参见说明）： 钙化性主动脉瓣狭窄（CAVS）是一种常见的临床问题，是第二常见的 心脏手术适应症。这些研究将确定三种新的治疗干预措施是否 可以减缓或逆转CAVS的进展。如果其中任何一种方法被证明是有效的， 减缓CAVS的进展，它可能导致从根本上改变CAVS临床治疗的临床研究。 CAVS。

Studies during the current period of funding have focused on cardiovascular effects of oxidative stress. The investigators observed oxidative stress in the aortic valve of "Reversa" (ldl"'7apoB^¿¿'^¿¿/Mttp'""/Mx1- Cre**) mice, and found that 1/3 ofthe mice develop moderately severe calcific aortic valvular stenosis (CAVS). The investigators now propose to test the hypotheses that 1) local and humoral mechanisms associated with oxidative stress and infiammation contribute to development of CAVS, and 2) mechanisms that reduce oxidative stress and infiammation inhibit development and progression of CAVS. A medical intervention to slow the progression of CAVS would be of great value. The invesfigators have demonstrated, with published and preliminary data, that two approaches can suppress signaling in the osteogenic pathway and reduce calcification of the aortic valve. Pharmacological interventions and complementary genetically altered mice will be used to examine mechanisms that may contribute to CAVS. The investigators will measure gene expression in aortic valves of mice, and function of the valve. One goal is to detennine whether osteoprotegerin (OPG), an endogenous decoy receptor of receptor- activator of NFKB ligand (RANKL), decreases expression of osteogenic genes, reduces calcification of the valve, and slows progression of aortic stenosis in mice with moderate aortic stenosis. Studies also are proposed to test the hypothesis that OPG deficiency (OPG"'' mice) accelerates CAVS. The second goal is to determine whether two interacting endogenous systems, renin-angiotensin and PPARy, modulate development of CAVS. One hypothesis is that ATI receptors contribute to development of CAVS. Studies are planned to determine whether an antagonist of ATI receptors (but not an angiotensin- converting enzyme inhibitor) decreases expression of osteogenic genes and inhibits development of CAVS in Reversa mice. Studies also are planned to test the hypothesis that susceptibility to CAVS is reduced in ATlr"'' mice. Finally, studies are planned to test the hypotheses that pioglitazone (a PPARy ligand) protects against development of CAVS in Reversa mice and, in endothelium-targeted dominant negative PPARy mice (E-V290M), susceptibility to CAVS is increased. The goal of this project is to use an experimental model of CAVS with hemodynamically significant stenosis to clarify molecular mechanisms of CAVS, functional consequences of calcification, and to explore possible therapeutic approaches. RELEVANCE (See instructions): Calcific aortic valve stenosis (CAVS) is a common clinical problem, and is the second most common indication for cardiac surgery. These studies will determine whether three novel therapeutic interventions may slow, or reverse, the progression of CAVS. If any one of these approaches proves to be effective in slowing progression of CAVS, it could lead to clinical studies that fundamentally alter clinical treatment of CAVS.