PATHWAY PHARMACOGENETICS AND ANGIOTENSIN RECEPTOR BLOCKER RESPONSES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 血管紧张素受体阻滞剂(ARB)通过血管紧张素II阻断和非血管紧张素II介导的特性，有利地影响糖脂代谢、脂肪细胞因子和心脏结构和功能。就ARB表现出的多种改善心血管(CV)风险的有益效果而言，这些药物代表着一种潜在的重要治疗方式，适用于不同的患者群体。然而，与大多数药物类别一样，患者对ARB的反应表现出巨大的变异性。最近的证据表明，ARB增加了血浆中抗动脉粥样硬化脂肪细胞因子脂联素的浓度。鉴于脂联素在预防胰岛素抵抗、血脂异常、动脉粥样硬化、心肌肥厚和缺血性损伤方面的中心作用，这种作用很重要。事实上，脂联素是几个分子通路的上游效应器，这些分子通路介导了无数的炎症和代谢生物过程。因此，编码脂联素的ADIPOQ基因是ARB反应的一个强有力的候选介体，ADIPOQ的遗传变异性可能会改变药物的反应。在这里，我们建议对具有代谢综合征特征的心肌梗死后患者进行一项固定序列、磨合期的ARB替米沙坦的临床研究，该研究具有深入的代谢表型和基因型特征。我们建议对ADIPOQ进行综合评估，以确定在心血管疾病进展中重要的分子和肌维终点方面，哪一遗传亚群(S)患者可能从替米沙坦中获得最大益处。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Through both angiotensin II-blocking and non-angiotensin II-mediated properties, angiotensin receptor blockers (ARBs) favorably affect glucose and lipid metabolism, adipocytokines and cardiac structure and function. to the extent that ARBs exhibit multiple beneficial effects that improve cardiovascular (CV) risk profiles, these agents represent a potentially important treatment modality for diverse patient populations. However, as with most drug classes, patients display tremendous variability in response to ARBs. Recent evidence suggests that ARBs increase plasma concentrations of the anti-atherosclerotic adipocytokines adiponectin. This effect is important given adiponectin's central role in protecting against insulin resistance, dyslipidemia, atherosclerosis, myocardial hypertrophy, and ischemic injury. In fact, adiponectin is an upstream effector of several molecular pathways that mediate myriad inflammatory and metabolic bioprocesses. As such, ADIPOQ, the gene that encodes adiponectin, is a strong candidate mediator of response to ARBs, and genetic variability in ADIPOQ could plausibly alter drug responses. Herein, we propose a fixed-sequence, run-in phase clinical study of the ARB telmisartan with in-depth metabolic phenotype and genotype characterization in post-myocardial infarction patients with features of the metabolic syndrome. We propose a comprehensive evaluation of ADIPOQ in order to determine which genetic subgroup(s) of patients might derive the greatest benefit from telmisartan with respect to molecular and myo-dimensional endpoints important in CV disease progression.