Cell Specific Mineralocorticoid Signaling, Insulin Resistance and Cardiovascular Stiffness

细胞特异性盐皮质激素信号传导、胰岛素抵抗和心血管僵硬

• 批准号: 10045558
• 负责人: Guido Lastra
• 金额: --
• 依托单位: HARRY S. TRUMAN MEMORIAL VA HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10045558
• 关键词: 1-Phosphatidylinositol 3-Kinase; A/J Mouse; Aldosterone; American; American Heart Association; Angiotensin II; Atomic Force Microscopy; Attenuated; Awareness; Bioavailable; Biochemical Pathway; Biological Availability; Blood Vessels; Carbohydrates; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cells; Collagen; Connective Tissue; Consumption; Data; Diabetes Mellitus; Diet; Dietary Intervention; Docking; Endothelial Cells; Endothelium; Environmental Risk Factor; Extracellular Matrix; FRAP1 gene; Fatty acid glycerol esters; Female; Fibrosis; Funding; Genetic; Glycocalyx; Goals; Grant; Health; Heart; Image; Impairment; In Vitro; Individual; Infiltration; Inflammation; Insulin; Insulin Resistance; Insulin Signaling Pathway; Intervention; Knock-out; Knockout Mice; Knowledge; Lead; Magnetic Resonance Imaging; Measures; Mediating; Metabolic; Mineralocorticoid Receptor; Mineralocorticoids; Modeling; Molecular; Morbidity - disease rate; Mus; Muscle; Nitric Oxide; Nitric Oxide Synthase; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Overnutrition; Overweight; PI3 gene; Phosphorylation; Physiologic pulse; Process; Proto-Oncogene Proteins c-akt; Rattus; Receptor Signaling; Relaxation; Research; Ribosomal Protein S6 Kinase; Rodent; Rodent Model; Role; Serine; Sex Differences; Sgk protein; Signal Pathway; Signal Transduction; Site; Skeletal Muscle; Structure; Sucrose; Techniques; Therapeutic; Time; Tissues; Translating; Type 2 diabetic; United States National Institutes of Health; Vascular Endothelial Cell; Veterans; Wild Type Mouse; Woman; Work; base; cardiovascular disorder risk; coronary fibrosis; crosslink; diet-induced obesity; enzyme activity; epithelial Na+ channel; extracellular; feeding; improved; in vivo; indexing; innovation; insight; insulin receptor substrate 1 protein; insulin signaling; knockout animal; lifetime risk; macrophage; male; men; monocyte; mortality; mouse model; novel; novel therapeutics; patch clamp; polymerization; prevent; receptor; recruit; saturated fat; transglutaminase 2; two photon microscopy; western diet

In my last funded VA merit I proposed to investigate novel molecular mechanisms by which angiotensin II (Ang II), aldosterone and a WD (high in saturated fat and refined carbohydrates individually and collectively promotes insulin (INS) resistance in cardiovascular (CV) and skeletal muscle tissue in male rodents. Because of the increasing awareness by the NIH, the VA, the American Diabetes Association and American Heart Association regarding incorporation of females in research, we performed comparable work in females. We have found that this diet has a more negative CV impact in females. This is of translational relevance to the VA because of increasing numbers of female veterans and because in conditions of INS resistance such as obesity and type 2 diabetes, women display a substantially increased risk for CVD. As the lifetime risk for overweight/obesity and diabetes in women is high, associated CVD in women has become a major health problem. As people become obese and INS resistant, they manifest increasing CV stiffness, an abnormality that tracks closely with increasing CVD. INS resistance in the heart and vasculature results in decreased bioavailable nitric oxide (NO) which is associated with increased CV stiffness. Reduced bioavailable NO results in increased activity of the enzyme transglutaminase 2 (TG2), which increases collagen crosslinking and associated heart and vascular stiffness. We have observed that females, but not males, develop CV stiffness after only 8 weeks of consumption of a WD. Our ongoing work in a female mouse model of INS resistance induced by a WD also demonstrates that mineralocorticoid receptor (MR) blockade improves heart and vascular INS resistance and stiffness. We have garnered evidence that selective knockout of the endothelial cell (EC) MR in female mice abrogates the reduction in CV INS metabolic signaling and CV stiffness and impaired relaxation induced by consumption of a WD for 16 weeks. The role of the ECMR in the genesis of sex-related differences in CV INS signaling and stiffness over time has not been explored. In this proposal, our central hypothesis is that ECMR activation promotes CV INS resistance and stiffness. The corollary to this hypothesis is that impairment in INS metabolic signaling reduces bioavailable NO, which results in extracellular release and activation of TG2 promoting collagen crosslinking and therefore CV stiffness in females and males. In this revised proposal we plan to use a novel rodent model of endothelial specific MR knockout mice fed a WD, as well as innovative techniques to access INS resistance and associated CV stiffness in vivo and ex vivo. In Objective 1, we will determine the role of ECMR-mediated EC stiffening and resultant relationship between impairment of INS metabolic signaling and CV fibrosis/stiffness and impaired relaxation in males and females consuming a WD. relationship between ECMR-mediated impairment of INS metabolic signaling and reduced bioavailable NO and CV stiffness in WD- fed mice. In Objective 2, we will determine the role of ECMR mediated EnNaC activation in promotion of CV INS resistance in relation to vascular and cardiac fibrosis/stiffness and impaired relaxation. We anticipate that results from this proposal will yield unique insights into the mechanisms of CVD in obese and type 2 diabetic Veteran men and women, with the goal of translating these findings into therapeutic strategies to reduce CVD, especially in overweight INS resistant men and women.

在我的最后一个资助的VA优点中，我提出了研究血管紧张素II的新型分子机制（ANG ii），醛固酮和WD（饱和脂肪和精制碳水化合物分别和共同促进 雄性啮齿动物中心血管（CV）和骨骼肌组织中的胰岛素（INS）耐药性。因为 NIH，VA，美国糖尿病协会和美国心脏协会提高了意识 关于在研究中纳入女性，我们在女性中进行了可比的工作。我们发现 这种饮食对女性的简历影响更大。这是与VA的转化相关性 越来越多的女性退伍军人，因为在诸如肥胖和2型等抗药性的情况下 糖尿病，女性表现出CVD的风险大大增加。作为超重/肥胖的终身风险 女性糖尿病很高，女性相关的CVD已成为一个主要的健康问题。随着人们的变化 肥胖和抗性，它们表现出越来越多的CV刚度，这种异常与随着增加的速度紧密跟踪 CVD。心脏和脉管系统中的抗性导致生物利用一氧化氮（NO）降低 与CV刚度增加有关。降低生物可利用的无结果酶的活性增加 转谷氨酰胺酶2（TG2）增加了胶原蛋白交联，相关的心脏和血管僵硬。 我们已经观察到，在WD消费仅8周后，女性而不是男性会形成简历僵硬。 我们在WD引起的INS抗性模型中正在进行的工作也表明 矿物皮质激素受体（MR）阻断可改善心脏和血管抗性和僵硬。我们有 获得的证据表明，雌性小鼠中内皮细胞（EC）MR的选择性敲除降低 在CV INS代谢信号传导和CV刚度以及WD消耗16 几周。 ECMR在CV INS信号传导和刚度的性别相关差异的起源中的作用 时间尚未探索。在此提案中，我们的中心假设是ECMR激活促进CV 阻力和刚度。该假设的推论是INS代谢的损害 信号传导降低了生物利用NO，这导致细胞外释放和TG2促进的激活 胶原蛋白交联，因此在女性和男性中的CV刚度。在此修订的建议中，我们计划 使用喂养WD的内皮特异性MR敲除小鼠的新型啮齿动物模型以及创新的技术 在体内和体内访问INS电阻和相关的CV刚度。在目标1中，我们将确定 ECMR介导的EC加强的作用和INS代谢信号损伤之间的结果关系 以及食用WD的男性和女性的CV纤维化/刚度和放松受损。之间的关系 ECMR介导的INS代谢信号传导的损伤以及WD-中的生物利用度NO和CV刚度降低 喂老鼠。在目标2中，我们将确定ECMR介导的ENNAC激活在促进CV中的作用 与血管和心脏纤维化/僵硬以及放松受损有关的INS耐药性。我们预料到这一点 该提案的结果将产生对肥胖和2型糖尿病中CVD机制的独特见解 老兵男女，目的是将这些发现转化为减少CVD的治疗策略， 尤其是在超重的女性和女人中。