Mechanisms and Consequences of Calcification in Aortic Valvular Stenosis

主动脉瓣狭窄钙化的机制和后果

• 批准号: 8378367
• 负责人: DONALD D HEISTAD
• 金额: $ 41.53万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8378367
• 关键词: AGTR2 gene; Address; Adipocytes; Affect; Agonist; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Anti-Inflammatory Agents; Antioxidants; Aortic Valve Stenosis; Apolipoproteins B; Cardiac Surgery procedures; Cardiovascular system; Clinical; Clinical Research; Clinical Treatment; Data; Development; Disease; Dominant-Negative Mutation; Elderly; Endothelium; Experimental Models; Functional disorder; Funding; Gene Expression; Genes; Goals; Hepatic; Inflammation; Instruction; Intervention; Lead; Ligands; Losartan; Measures; Medical; Molecular; Mus; NF-kappa B; Osteoblasts; Oxidative Stress; Pathway interactions; Peptidyl-Dipeptidase A; Pioglitazone; Play; Predisposition; Proteins; Publishing; Reading; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System; Research Personnel; Role; Sclerosis; Severities; Signal Transduction; Staging; Stem cells; Stenosis; Stress; Superoxides; System; Testing; Therapeutic; Tumor necrosis factor receptor 11b; advanced disease; aortic valve; calcification; hypercholesterolemia; novel therapeutic intervention; osteogenic; prevent; programs; receptor

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.

在目前的资助期间，研究重点是氧化应激对心血管的影响。 研究人员观察到“Reversa”(低密度脂蛋白)(‘7apoB’/mtp‘“”/mx1-)的主动脉瓣中的氧化应激。 Cre**)小鼠，发现1/3的小鼠发展为中度重度钙化性主动脉瓣狭窄。 (骑士队)研究人员现在提议检验以下假设：1)局部和体液机制 与氧化应激和炎症有关，有助于CAV的发展，以及2)机制 减少氧化应激和炎症，抑制CAV的发展和进展。 通过医疗干预来减缓骑士队的发展将是非常有价值的。投资方拥有 用已公布的初步数据证明，有两种方法可以抑制 成骨途径和减少主动脉瓣的钙化。药理干预和 互补的转基因小鼠将被用来检查可能导致CAVS的机制。 研究人员将测量小鼠主动脉瓣中的基因表达，以及瓣膜的功能。 一个目标是确定骨保护素(OPG)，一种内源性受体诱饵受体- NFKB配体激活剂(RANKL)，减少成骨基因的表达，减少骨组织的钙化 并延缓中度主动脉狭窄小鼠主动脉狭窄的进展。研究也是 提出检验OPG缺乏(OPG“‘’老鼠)加速CAV的假说。 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，调制骑士队的发展。一种假说是ATI受体参与了糖尿病的发生。 骑士队。计划进行研究以确定ATI受体的拮抗剂(但不是血管紧张素-1) 转化酶抑制剂)减少成骨基因表达，抑制CAV的发展 在反转的小鼠身上。研究还计划检验这样一种假设，即人对CAV的易感性在 最后，研究计划检验吡格列酮(一种PPARy配体)保护小鼠的假说 在逆转小鼠和内皮靶向显性阴性PPARy小鼠中抑制CAVS的发育 (E-V290M)，对CAVs的易感性增加。 本项目的目标是使用一个具有血流动力学意义的Cavs实验模型 阐明腔静脉狭窄的分子机制，钙化的功能后果，并探讨 可能的治疗方法。 相关性(请参阅说明)： 钙化性主动脉瓣狭窄(CAVS)是一种常见的临床问题，也是第二常见的 心脏手术的适应症。这些研究将确定三种新的治疗干预措施 可能会减缓或逆转骑士队的进步。如果这些方法中的任何一个被证明是有效的 减缓CAV的进展，可能导致从根本上改变CAV临床治疗的临床研究 骑士队。