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

基本信息

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
项目类别：
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

项目摘要

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.

在我上次资助的 VA 项目中，我提议研究血管紧张素 II (Ang II)、醛固酮和WD（高饱和脂肪和精制碳水化合物单独和共同促进雄性啮齿动物心血管（CV）和骨骼肌组织中的胰岛素（INS）抵抗。因为 NIH、VA、美国糖尿病协会和美国心脏协会提高认识关于将女性纳入研究，我们在女性中进行了类似的工作。我们发现这种饮食对女性的心血管影响更大。这与 VA 具有转化相关性，因为女性退伍军人数量不断增加，并且由于肥胖和 2 型等 INS 耐药情况糖尿病，女性患 CVD 的风险显着增加。由于超重/肥胖的终生风险和女性糖尿病发病率较高，与之相关的CVD已成为女性的一大健康问题。当人们成为肥胖且具有 INS 抗性，他们表现出 CV 硬度增加，这种异常与增加密切相关化学气相沉积。心脏和脉管系统中的 INS 抵抗导致生物可利用的一氧化氮 (NO) 减少，与CV硬度增加有关。生物可利用的一氧化氮减少导致酶活性增加转谷氨酰胺酶 2 (TG2)，可增加胶原蛋白交联以及相关的心脏和血管硬度。我们观察到，女性（而非男性）在服用 WD 仅 8 周后就会出现心血管僵硬。我们正在进行的由 WD 诱导的 INS 抗性雌性小鼠模型的研究也表明盐皮质激素受体 (MR) 阻断可改善心脏和血管 INS 阻力和僵硬度。我们有获得的证据表明，选择性敲除雌性小鼠的内皮细胞 (EC) MR 可消除这种减少在 CV INS 代谢信号传导和 CV 僵硬以及因食用 WD 16 引起的松弛受损中几周。 ECMR 在 CV INS 信号传导和刚度性别相关差异的发生中的作用时间还没有探索过。在这个提案中，我们的中心假设是 ECMR 激活促进 CV INS 阻力和刚度。这一假设的推论是 INS 代谢受损信号传导减少生物可利用的 NO，导致细胞外释放并激活 TG2，促进胶原蛋白交联，从而导致女性和男性的心血管僵硬度。在这个修订后的提案中，我们计划使用一种新型啮齿动物模型，即内皮特异性 MR 敲除小鼠，喂食 WD 以及创新技术获取体内和体外的 INS 阻力和相关的 CV 硬度。在目标 1 中，我们将确定 ECMR介导的EC硬化的作用与INS代谢信号损伤之间的关系服用 WD 的男性和女性的心血管纤维化/僵硬和松弛受损。之间的关系 ECMR 介导的 INS 代谢信号损伤以及 WD 中生物可利用的 NO 和 CV 硬度的降低喂老鼠。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 INS 阻力与血管和心脏纤维化/僵硬以及松弛受损有关。我们预计该提案的结果将对肥胖和 2 型糖尿病患者的 CVD 机制产生独特的见解经验丰富的男性和女性，目标是将这些发现转化为减少心血管疾病的治疗策略，尤其是超重的 INS 抵抗男性和女性。