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（由申请人提供）：高血压是一种常见疾病，其特征是血管舒张张张力增加，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异常。 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活性和高血压。但是，尽管这些发现表明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理或维持。在此提案中，我们将通过利用最近产生的转基因小鼠的病理生理意义来选择性地过表达G1I2或G1I2抑制性“微基因”平滑肌中的病理生理意义。初步实验表明，来自G1I2过表达小鼠的动脉环比其非转基因同窝仔的动脉环产生的收缩力明显更大。这是一个重要的观察结果，因为它提供了第一个直接将VSM中G1I2表达水平与血管舒缩反应性联系起来的证据。此外，单独增加G1I2表达的发现足以增加VSM的血管收缩反应为总体假设提供支持的基本原理：VSM中G1I2表达/活性的诱导是发病机理和/或维持高血压的中心事件。为了检验这一假设，AIM 1将研究体内模型中G1I2诱导在VSM中的重要性。在急性加压剂/血管扩张剂挑战之后，以及在实验诱导的高血压期间，将评估具有G1I2在VSM中G1I2增强表达的转基因小鼠的血压和心脏功能。 AIM 2将确定G1I2调节VSM响应性的机制。因为初步数据表明，来自G1I2过表达器和非转基因小鼠的培养的VSM细胞中激动剂诱导的细胞内钙通量的大小没有差异，因此该目标将集中在钙敏化作为G1I2增强血管接收的主要机制上。 AIM 3将使用在VSM中表达G1I2抑制性“微基”的转基因小鼠，以确定VSM中G1I2信号传导的抑制是否可以预防或减弱血管舒缩性过度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高血压中G1I2信号传导的作用，从而可能导致靶向G1I2而不是单个G蛋白偶联受体的新型降压疗法。公共卫生相关性：高血压是一种高度普遍的疾病，是心脏病和中风的主要危险因素。高血压的G蛋白受体信号传导异常可能通过增加收缩和损害动脉松弛而导致血压升高。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型策略。