The Role Gai2 Signaling in Hypertension

Gai2 信号转导在高血压中的作用

• 批准号: 7920243
• 负责人: Dennis W McGraw
• 金额: $ 39.25万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7920243
• 关键词: Acute; Adenylate Cyclase; Adult; Affect; Agonist; American; Angiotensin II; Animals; Antihypertensive Agents; Arteries; Attenuated; Bathing; Biology; Blood Pressure; Blood Vessels; Calcium; Cardiac; Caucasians; Caucasoid Race; Cells; Coupled; DOCA; Data; Defect; Development; Disease; Event; Exhibits; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genetic; Genetic Polymorphism; Heart Diseases; Human; Hypertension; Hypertrophy; Individual; Inflammation; Investigation; Laboratories; Lead; Link; Maintenance; Measures; Mediating; Monitor; Mus; Myosin Light Chains; NG-Nitroarginine Methyl Ester; Organ; Pathogenesis; Peripheral; Pertussis Toxin; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physiological; Physiology; Play; Preparation; Protein Subunits; Receptor Signaling; Relaxation; Risk Factors; Rodent; Role; Signal Pathway; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Sodium Chloride; Stroke; Structure; System; Testing; Transgenic Mice; Vascular Smooth Muscle; Vascular resistance; Vasoconstrictor Agents; Vasodilator Agents; Vasomotor; base; blood pressure regulation; hemodynamics; human subject; improved; in vitro Assay; in vivo; in vivo Model; inhibitor/antagonist; innovation; interest; non-genetic; novel; novel strategies; overexpression; prevent; public health relevance; receptor; release of sequestered calcium ion into cytoplasm; research study; response; vasoconstriction

DESCRIPTION (provided by applicant): Hypertension is a common disease characterized by increased vasomotor tone, smooth muscle remodeling and vessel inflammation. These aspects of vascular smooth muscle (VSM) biology are extensively regulated by G-protein-coupled signal transduction, which can be abnormal in the hypertensive state. In this regard, G1i2 has generated interest because (a) G1i2 expression and activity are increased in VSM and other cells from hypertensive animals and humans, (b) inhibition of G1i2 with pertussis toxin has an antihypertensive effect in rodents with genetic and non-genetic forms of hypertension, and (c) polymorphisms in the G23 subunit of the Gi heterotrimer are associated with increased G1i2 activity and hypertension. However, while these findings indicate that G1i2-dependent signaling can influence blood pressure control, it is unclear whether an increase in G1i2 expression/activity in VSM contributes to the pathogenesis or maintenance of the hypertensive state. In this proposal, we will interrogate the pathophysiological significance of altered G1i2 signaling in VSM by taking advantage of recently generated transgenic mice that selectively overexpress either G1i2 or a G1i2 inhibitory 'minigene' in smooth muscle. Preliminary experiments show that arterial rings from the G1i2 overexpressing mice generate significantly greater contractile forces than arterial rings from their nontransgenic littermates. This is a significant observation because it provides the first evidence that directly links the level of G1i2 expression in VSM to vasomotor responsiveness. Moreover, the finding that increased G1i2 expression alone is sufficient to increase the vasoconstrictor response of VSM provides supporting rationale for the overall hypothesis: the induction of G1i2 expression/activity in VSM is a central event in the pathogenesis and/or maintenance of hypertension. To examine this hypothesis, Aim 1 will investigate the significance of G1i2 induction in VSM in an in vivo model. Blood pressure and cardiac function in transgenic mice with augmented expression of G1i2 in VSM will be assessed following acute vasopressor/vasodilator challenges, and during experimentally induced hypertension. Aim 2 will determine the mechanism(s) by which G1i2 regulates VSM responsiveness. Because preliminary data show that the magnitude of agonist-induced intracellular calcium fluxes in cultured VSM cells from G1i2 overexpressors and nontransgenic mice do not differ, this aim will focus on calcium sensitization as the primary mechanism by which G1i2 enhances vasoconstriction. Aim 3 will use transgenic mice that express a G1i2 inhibitory 'minigene' in VSM to determine whether inhibition of G1i2 signaling in VSM can prevent or attenuate the development of vasomotor hyperresponsiveness and hypertension. The successful completion of these aims will directly substantiate or refute a role for altered G1i2 signaling in hypertension, and thereby could lead to novel antihypertensive therapies that target G1i2 rather than individual G-protein-coupled receptors. PUBLIC HEALTH RELEVANCE: Hypertension is a highly prevalent disease that is a major risk factor for cardiac disease and stroke. G-protein receptor signaling abnormalities in hypertension may contribute to elevated blood pressure by enhancing contraction and impairing relaxation of arteries. Successful completion of these studies may improve our understanding of these abnormalities, and thereby could ultimately lead to novel strategies to treat hypertension.

描述（申请人提供）：高血压是一种常见疾病，其特征是血管舒缩张力增加、平滑肌重塑和血管炎症。血管平滑肌 (VSM) 生物学的这些方面受到 G 蛋白偶联信号转导的广泛调节，在高血压状态下可能会出现异常。在这方面，G1i2引起了人们的兴趣，因为（a）G1i2在高血压动物和人类的VSM和其他细胞中表达和活性增加，（b）用百日咳毒素抑制G1i2对患有遗传性和非遗传性高血压的啮齿动物具有抗高血压作用，以及（c）Gi异源三聚体的G23亚基的多态性与增加 G1i2 活性和高血压。然而，虽然这些发现表明 G1i2 依赖性信号传导可以影响血压控制，但尚不清楚 VSM 中 G1i2 表达/活性的增加是否有助于高血压状态的发病机制或维持。在本提案中，我们将利用最近生成的在平滑肌中选择性过度表达 G1i2 或 G1i2 抑制性“小基因”的转基因小鼠，探讨 VSM 中 G1i2 信号传导改变的病理生理学意义。初步实验表明，G1i2 过表达小鼠的动脉环比非转基因同窝小鼠的动脉环产生明显更大的收缩力。这是一个重要的观察结果，因为它提供了第一个证据，证明 VSM 中 G1i2 表达水平与血管舒缩反应性直接相关。此外，仅增加 G1i2 表达就足以增加 VSM 的血管收缩反应，这一发现为总体假设提供了支持依据：VSM 中 G1i2 表达/活性的诱导是高血压发病机制和/或维持的中心事件。为了检验这一假设，目标 1 将在体内模型中研究 VSM 中 G1i2 诱导的重要性。 VSM 中 G1i2 表达增强的转基因小鼠的血压和心脏功能将在急性血管加压剂/血管舒张剂挑战后以及实验诱导的高血压期间进行评估。目标 2 将确定 G1i2 调节 VSM 响应性的机制。因为初步数据表明，G1i2 过表达者和非转基因小鼠培养的 VSM 细胞中激动剂诱导的细胞内钙通量的大小没有差异，因此本目标将集中于钙敏化，作为 G1i2 增强血管收缩的主要机制。目标 3 将使用在 VSM 中表达 G1i2 抑制性“小基因”的转基因小鼠来确定 VSM 中 G1i2 信号传导的抑制是否可以预防或减轻血管舒缩高反应性和高血压的发展。这些目标的成功完成将直接证实或反驳 G1i2 信号传导改变在高血压中的作用，从而可能导致针对 G1i2 而不是单个 G 蛋白偶联受体的新型抗高血压疗法。公共卫生相关性：高血压是一种高度流行的疾病，是心脏病和中风的主要危险因素。高血压中的 G 蛋白受体信号异常可能通过增强动脉收缩和削弱动脉舒张而导致血压升高。这些研究的成功完成可能会提高我们对这些异常的理解，从而最终可能导致治疗高血压的新策略。