Role of Gap Junction in Hypoxia-induced Pulmonary Hypertension

间隙连接在缺氧引起的肺动脉高压中的作用

基本信息

批准号：
10120518
负责人：
Ayako Makino
金额：
$ 39.38万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10120518
关键词：
Acute Altitude Altitude Sickness Alveolar Animals Arteries Attenuated Blood Pressure Blood Vessels Calcium-Activated Potassium Channel Caliber Cardiovascular Diseases Cell Hypoxia Cells Cessation of life Chronic Chronic Obstructive Airway Disease Data Development Diabetes Mellitus Diabetic mouse Distal Down-Regulation Electric Capacitance Endothelial Cells Endothelium Epoprostenol Exhibits Functional disorder Gap Junctions Genes Genetic Goals Heart failure Hyperglycemia Hypoxia Impairment Intercellular Junctions Interstitial Lung Diseases Lesion Lung Mediating Messenger RNA Molecular Morbidity - disease rate Mus Muscle Contraction Nitric Oxide Non-Insulin-Dependent Diabetes Mellitus Pathogenicity Pathologic Patients Pharmaceutical Preparations Population Predisposition Progressive Disease Prostaglandins I Proteins Pulmonary Heart Disease Pulmonary Hypertension Pulmonary Vascular Resistance Pulmonary artery structure RNA Relaxation Reporting Risk Factors Role Severities Signal Transduction Sleep Smooth Muscle Smooth Muscle Myocytes Systolic Pressure Testing Vascular remodeling Vasodilation Ventricular arterial stiffness base clinically relevant connexin 40 diabetic patient endothelial dysfunction mortality overexpression personalized medicine pressure small molecule statistics vascular abnormality vascular endothelial dysfunction vasoconstriction

项目摘要

Project Summary/Abstract Hypoxia induces pulmonary vasoconstriction by increasing smooth muscle contraction and attenuating endothelium-dependent relaxation (EDR). Sustained pulmonary vasoconstriction and subsequent vascular remodeling in small distal pulmonary artery (PA) are the major causes for the increased pulmonary vascular resistance in patients with hypoxia-induced pulmonary hypertension (HPH). Endothelial dysfunction is implicated in the development of many cardiovascular diseases including HPH and diabetes. EDR is mediated via different mechanisms in small distal and large proximal arteries. Vasodilation in large proximal artery is mainly caused by endothelium-derived nitric oxide (NO) and/or prostacyclin (PGI2), while vasodilation in small distal artery is due prominently to endothelium-derived hyperpolarization (EDH). Gap junction (GJ) is an intercellular junction that transfers small molecules and propagates electric signals (e.g., hyperpolarization) to adjacent cells. GJ is more abundant in small distal artery compared to large proximal artery. We recently reported that diabetic mice exhibited significantly increased sensitivity to develop HPH and diabetic patients have higher susceptibility to develop pulmonary vascular abnormalities. It is, however, unknown whether alteration of endothelial function in diabetes is involved in determining severity of HPH. The goal of this study is to investigate a) if and how endothelial dysfunction in small distal PAs, as a result of dysfunctional GJ in endothelial cells (ECs), contributes to the development and progression of HPH and b) if and how diabetes-associated GJ dysfunction exacerbates HPH. Our preliminary data demonstrate that: i) small distal (4th-5th order) PAs, but not large proximal (1st-2nd order) PAs, exhibit great EDH-dependent relaxation that can be attenuated by hypoxia; ii) pulmonary ECs from HPH mice show lower protein level of connexin 40 (Cx40, a component of GJ) than ECs from normoxic mice; iii) hypoxia attenuates GJ activity in pulmonary ECs, iv) Cx40 overexpression enhances EDH-dependent relaxation and decreases right ventricular systolic pressure in HPH mice; v) hypoxic diabetic mice exhibit attenuated EDR in small (4th-5th) PAs compared to hypoxic control mice; and vi) pulmonary ECs from diabetic mice show lower Cx40 mRNA level than ECs from control mice. Based on these preliminary data, we hypothesize that a) chronic hypoxia downregulates Cx40 expression, attenuates GJ function, impairs EDH-dependent relaxation in small (4th-5th) PAs and, ultimately, induces HPH; and b) diabetes increases the susceptibility to HPH due to decreased GJ activity. The specific aims are 1) to identify the molecular mechanisms by which chronic hypoxia attenuates endothelial function in small distal PAs, 2) to investigate the pathogenic role of Cx40 in the development of HPH, and 3) to examine the effect of type 2 diabetes on the development of HPH with a special focus on endothelial GJ function. Completion of the proposed study will shed great lights into developing personalized therapies for diabetic patients living at high altitude and/or have hypoxic cardiopulmonary diseases.

项目概要/摘要缺氧通过增加平滑肌收缩和减弱来诱导肺血管收缩内皮依赖性舒张（EDR）。持续的肺血管收缩和随后的血管收缩远端小肺动脉（PA）重塑是肺血管增加的主要原因缺氧引起的肺动脉高压（HPH）患者的抵抗力。涉及内皮功能障碍包括 HPH 和糖尿病在内的许多心血管疾病的发展。 EDR 通过不同的方式介导远端小动脉和近端大动脉的机制。近端大动脉的血管舒张主要是由内皮源性一氧化氮（NO）和/或前列环素（PGI2），而远端小动脉的血管舒张是由于主要是内皮源性超极化（EDH）。间隙连接 (GJ) 是一种细胞间连接转移小分子并将电信号（例如超极化）传播到相邻细胞。 GJ更多与近端大动脉相比，远端小动脉丰富。我们最近报道了糖尿病小鼠表现出对 HPH 的敏感性显着增加，糖尿病患者对 HPH 的易感性更高出现肺血管异常。然而，目前尚不清楚内皮功能的改变是否会导致糖尿病与 HPH 严重程度的确定有关。本研究的目的是调查 a) 是否以及如何由于内皮细胞 (EC) 功能失调的 GJ，导致小远端 PA 的内皮功能障碍，导致 b) 糖尿病相关的 GJ 功能障碍是否以及如何恶化健康PH。我们的初步数据表明：i）小的远端（第 4-5 阶）PA，但不是大的近端（第 1-2 阶）PA 顺序）PA，表现出很强的 EDH 依赖性松弛，可因缺氧而减弱； ii) 肺内皮细胞 HPH 小鼠的连接蛋白 40（Cx40，GJ 的一个组成部分）的蛋白水平低于常氧小鼠的 EC；三）缺氧减弱肺 EC 中的 GJ 活性，iv) Cx40 过表达增强 EDH 依赖性松弛并降低 HPH 小鼠的右心室收缩压； v) 缺氧糖尿病小鼠表现出 EDR 减弱与缺氧对照小鼠相比，在小（第 4-5 个）PA 中； vi) 糖尿病小鼠的肺 EC 显示较低 Cx40 mRNA 水平高于对照小鼠的 EC。根据这些初步数据，我们假设 a) 慢性缺氧会下调 Cx40 表达，削弱 GJ 功能，损害小细胞中 EDH 依赖性松弛 (4th-5th) PAs，最终诱导 HPH； b) 糖尿病会增加对 HPH 的易感性，因为 GJ 活动。具体目标是 1) 确定慢性缺氧减弱的分子机制小远端 PA 中的内皮功能，2) 研究 Cx40 在 HPH 发展中的致病作用， 3) 检查 2 型糖尿病对 HPH 发展的影响，特别关注内皮细胞 GJ 功能。拟议研究的完成将为开发个性化疗法提供重要线索居住在高海拔地区的糖尿病患者和/或患有缺氧性心肺疾病的患者。