Mechanisms for Sex Differences in CVD Pathology and Development of a Targeted Therapeutic

CVD 病理学性别差异的机制和靶向治疗的开发

• 批准号: 10053450
• 负责人: Iris Z Jaffe
• 金额: $ 69.3万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-15 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10053450
• 关键词: ACVR1 gene; ACVRL1 gene; Activins; Acute; Age; Agonist; Antihypertensive Agents; Attenuated; Biology; Blood Vessels; Blood capillaries; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cells; Cholesterol; Chronic; Chronic Disease; Cicatrix; Clinical; Code; Data; Development; Diabetes Mellitus; Diagnosis; Echocardiography; Female; Fibrosis; Gene Expression; Goals; Heart; Heart Hypertrophy; Histopathology; Human; Hypertension; Hypertrophy; Impairment; In Vitro; Injury; Legal patent; Link; Literature; Mechanics; Medical center; Menopause; Messenger RNA; Meta-Analysis; Methods; Microcirculation; Mineralocorticoid Receptor; Modeling; Molecular; Mus; Myocardial dysfunction; Myopathy; NR3C2 gene; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Pathogenesis; Pathologic; Pathology; Pathway interactions; Peptides; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Physiological; Postmenopause; Premenopause; Problem Solving; Proteins; Pulse Pressure; Rattus; Receptor Activation; Receptor Signaling; Renal function; Reporting; Research; Research Personnel; Rodent Model; Role; Serum; Severities; Sex Differences; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Sodium Chloride; Stress; Structure; Testing; Thinness; Type 2 Angiotensin II Receptor; Vascular Diseases; Vascular Smooth Muscle; Woman; Work; arterial stiffness; base; cardioprotection; clinically relevant; comorbidity; density; diabetic; diabetic rat; heart damage; improved; male; men; mouse model; non-diabetic; novel; novel therapeutic intervention; novel therapeutics; preclinical study; receptor expression; sex; success; targeted treatment; vascular injury

Summary: Cardiovascular Disease (CVD) remains the leading cause of death worldwide and is linked to a variety of co- morbidities including Type 2 Diabetes Mellitus (T2DM), and Obesity. Work over the last 20 years by our group and others have identified the Angiotensin II Type 2 Receptor (AT2R) as a key player in the development and pathogenesis of cardiac and vascular structural damage. Clinically, in men, loss of Agtr2 expression is associated with increased arterial stiffness, impaired kidney function, and increased pulse pressure. Literature shows that female-specific increase in AT2R expression protects murine female models from vascular injury. Healthy female (ZL-F) rats have higher cardiac expression of the X-linked Agtr2 compared to male (ZL-M) rats; but T2DM suppressed cardiac Agtr2 expression only in ZDF-F (female), not in ZDF-M (male). We posit that increasing Agtr2 expression in ZDF-F rat heart will render protection from cardiomyocyte loss and scarring and this treatment will be of particular benefit to women suffering from CVD. However, there are no AT2R agonists that can increase Agtr2 expression. We observed that NP-6A4, a novel peptide agonist of AT2R, could increase Agtr2 expression in rat and human CV cells and mitigate cardiac hypertrophy, fibrosis and capillary rarefaction in male Zucker obese rats. Our conceptually novel central hypothesis is based on these observations and states that NP-6A4-AT2R-signaling offers a new therapeutic approach to mitigate sex differences in CVD by increasing Agtr2 gene expression. We discovered two new cross-talks induced by NP- 6A4-AT2R; first is activation of ALK2-ALK1 pathway that mitigates capillary rarefaction, and the second is suppression of the mineralocorticoid receptor (MR) involved in pathological CV remodeling. In Aim 1, we will validate our hypothesis that NP-6A4 improves structural and functional cardiac and vascular parameters in rat models with chronic CVD induced by T2DM via increasing Agtr2 expression and signaling. We will use our new methods of detecting subclinical damage and subsequent protective remodeling via speckle tracking echocardiography (STE) in combination with histopathology, and extensive molecular signaling approaches. In Aim 2, we will investigate if NP-6A4 mitigates cardiac and vascular structural damage caused by acute mechanical- and drug-induced injury. We will also investigate a) the role of cross-talk between NP-6A4-AT2R and the Activin-like kinases (ALK2-ALK1 pathway) in improving capillary density, and b) the significance of the cross-talk between NP-6A4-AT2R and MR in mitigating pathological cardiovascular remodeling. Collectively, positive results of this study will have high clinical relevance since they validate a) the efficacy of NP-6A4 as a novel therapeutic for acute and chronic CVD, and for mitigating sex differences in CVD, and b) the efficacy of STE-based diagnosis of the progression and mitigation of T2DM-induced subclinical cardiovascular damage.

总结： 心血管疾病（CVD）仍然是全球死亡的主要原因，并与各种并发症有关。 包括2型糖尿病（T2DM）和肥胖症在内的疾病。我们团队在过去20年的工作 和其他人已经确定血管紧张素II 2型受体（AT2R）作为发展的关键角色， 心脏和血管结构损伤的发病机制。临床上，在男性中，Agtr2表达的缺失是 与动脉硬化增加、肾功能受损和脉压增加相关。文学 显示AT2R表达的雌性特异性增加保护鼠雌性模型免受血管损伤。 与雄性大鼠（ZL-M）相比，健康雌性大鼠（ZL-F）具有较高的X连锁Agtr2心脏表达; 但T2DM仅抑制ZDF-F（雌性）的心脏Agtr2表达，而不抑制ZDF-M（雄性）。我们将其 ZDF-F大鼠心脏中Agtr2表达的增加将保护心肌细胞免于损失和瘢痕形成， 这种治疗对患有心血管疾病的妇女特别有益。然而，没有AT2R激动剂 可以增加Agtr2的表达。我们观察到，NP-6A4，一种新的AT2R肽激动剂， 增加大鼠和人CV细胞中Agtr2表达并减轻心脏肥大、纤维化和毛细血管 在雄性Zucker肥胖大鼠中的稀疏。我们的概念新颖的中心假设是基于这些 观察并指出，NP-6A4-AT2R信号提供了一种新的治疗方法，以减轻性别 通过增加Agtr2基因表达来改善CVD。我们发现了两个新的由NP引起的串扰- 6A4-AT2R;第一个是ALK 2-ALK 1通路的激活，其减轻毛细血管稀疏，第二个是 抑制参与病理性CV重塑的盐皮质激素受体（MR）。在目标1中，我们 验证了我们的假设，即NP-6A4改善大鼠心脏和血管的结构和功能参数 通过增加Agtr2表达和信号传导，建立T2DM诱导的慢性CVD模型。我们将使用新的 通过斑点跟踪检测亚临床损伤和随后的保护性重塑的方法 超声心动图（STE）结合组织病理学和广泛的分子信号传导方法。在 目的2，我们将研究NP-6A4是否减轻急性心肌梗死引起的心脏和血管结构损伤。 机械和药物引起的损伤。我们还将调查a）NP-6A4-AT 2 R之间串扰的作用 和激活素样激酶（ALK 2-ALK 1通路）在改善毛细血管密度中的作用，和B）激活素样激酶（ALK 2-ALK 1通路）在改善毛细血管密度中的作用， NP-6A4-AT2R和MR之间的串扰减轻病理性心血管重构。总的来说， 本研究的阳性结果将具有高度的临床相关性，因为它们证实了a）NP-6A4作为 用于急性和慢性CVD以及用于减轻CVD中的性别差异的新治疗剂，和B）以下的功效： 基于ST诊断T2DM诱导的亚临床心血管损伤的进展和缓解。