The Role Gai2 Signaling in Hypertension

Gai2 信号转导在高血压中的作用

• 批准号: 8289577
• 负责人: Dennis W McGraw
• 金额: $ 38.86万
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8289577
• 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; Health; 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; 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（由申请人提供）：高血压是一种常见疾病，其特征为血管紧张素升高、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，这在高血压状态下可能是异常的。在这方面，G1 i2引起了人们的兴趣，因为（a）在高血压动物和人的VSM和其它细胞中G1 i2的表达和活性增加，（B）用百日咳毒素抑制G1 i2在具有遗传和非遗传形式的高血压的啮齿动物中具有抗高血压作用，和（c）Gi异源三聚体的G23亚基中的多态性与G1 i2活性增加和高血压相关。然而，虽然这些研究结果表明，G1 i2依赖性信号可以影响血压控制，目前还不清楚是否在VSM中G1 i2表达/活性的增加有助于高血压状态的发病机制或维持。在这个建议中，我们将询问的病理生理意义改变G1 i2信号在VSM中，利用最近产生的转基因小鼠，选择性过表达G1 i2或G1 i2抑制'minigene'在平滑肌。初步实验表明，G1 i2过表达小鼠的动脉环比非转基因同窝小鼠的动脉环产生更大的收缩力。这是一个重要的观察结果，因为它提供了第一个证据，直接联系在VSM中的G1 i2表达水平的血管反应。此外，单独增加G1 i2表达足以增加VSM的血管收缩反应的发现为以下总体假设提供了支持依据：VSM中G1 i2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，目的1将在体内模型中研究VSM中G1 i2诱导的意义。将在急性血管加压剂/血管扩张剂激发后和实验诱导的高血压期间评估VSM中G1 i2表达增强的转基因小鼠的血压和心脏功能。目的2将确定G1 i2调节VSM反应性的机制。由于初步数据表明，激动剂诱导的细胞内钙流量的大小在培养的VSM细胞从G1 i2过表达和非转基因小鼠没有什么不同，这个目标将集中在钙敏感的主要机制，G1 i2增强血管收缩。目的3将使用在VSM中表达G1 i2抑制性“小基因”的转基因小鼠来确定在VSM中抑制G1 i2信号传导是否可以预防或减轻血管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改变G1 i2信号在高血压中的作用，从而可能导致靶向G1 i2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蛋白受体信号传导异常可能通过增强动脉收缩和损害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，从而最终导致治疗高血压的新策略。