Cardiovascular Effect of the Vitamin D Endocrine System.

维生素 D 内分泌系统对心血管的影响。

• 批准号: 7393847
• 负责人: Yan Chun LI
• 金额: $ 37.86万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-15 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7393847
• 关键词: Accounting; Anabolism; Animal Model; Antihypertensive Agents; Atherosclerosis; Blood Pressure; Calcitriol; Calcium; Cardiovascular Physiology; Cardiovascular system; Cells; Cessation of life; Clinical; Clip; Cultured Cells; Cyclic AMP Response Element; DNA; Data; Disruption; Distal; Electrolytes; Endocrine; Endocrine system; Environment; Essential Hypertension; Gene Expression; Genes; Genetic Transcription; Goals; Hand; Heart Hypertrophy; Hemodialysis; High Blood Pressure; Human; Hypertension; Hypocalcemia result; Hypotension; Inbred SHR Rats; Kidney; Knock-out; Knockout Mice; Maintenance; Mediating; Molecular; Mus; Myocardial Infarction; Parathyroid Hormones; Patients; Personal Satisfaction; Physiological; Physiology; Plasma; Play; Population; Production; Protein Biosynthesis; Protein Overexpression; Proteins; Purpose; Rattus; Regulation; Renin; Renin-Angiotensin System; Repression; Risk Factors; Role; Secondary Hyperparathyroidism; Serum; Signal Transduction; Stroke; Testing; Therapeutic; Transcriptional Activation; Transgenes; Transgenic Mice; Transgenic Organisms; Up-Regulation; Vitamin D; Vitamin D Analog; Vitamin D3 Receptor; analog; base; blood pressure regulation; cardiovascular risk factor; extracellular; gain of function; gene repression; high renin hypertension; human PTH protein; in vivo; inhibitor/antagonist; novel; promoter

DESCRIPTION (provided by applicant): Accumulating clinical and experimental evidence has supported an important role of the vitamin D endocrine system in the regulation of cardiovascular functions. For instance, vitamin D therapy has been shown to significantly reduce the risk of cardiovascular death among hemodialysis patients. The renin-angiotensin system (RAS) plays a central role in the maintenance of electrolyte, extracellular volume and blood pressure homeostasis; over-activation of the RAS has been well known to cause cardiovascular problems such as hypertension, cardiac hypertrophy and atherosclerosis. In the past years we had obtained a great deal of evidence demonstrating that vitamin D regulates the RAS by suppressing renin biosynthesis. We found that disruption of the vitamin D signaling in mice results in activation of the RAS, leading to high blood pressure and cardiac hypertrophy, and that 1,25-dihydroxyvitamin D3 directly suppresses renin gene transcription by a VDR-dependent mechanism. In this application, we will continue to explore the physiological and pharmacological effects of vitamin D on the RAS by proposing three Specific Aims. The first Aim is to further define the role of vitamin D and parathyroid hormone (PTH) in the regulation of the RAS in vivo by transgenic approach. We will study transgenic (Tg) mice overexpressing human (h) VDR in renin-producing JG cells as well as VDR knockout (KO) mice that express the hVDR transgene (VDRKO-hVDR) only in JG cells. Parallel analyses of wild-type, VDRKO, Tg-hVDR and VDRKO-hVDR mice will allow us to further clarify the in vivo role of vitamin D and PTH in the regulation of renin gene expression. The second Aim is to elucidate the molecular mechanism underlying the regulation of renin gene expression by vitamin D. Based on our existing evidence, we will focus on exploring two indirect mechanisms: one is that vitamin D suppresses renin expression via stimulating other transcriptional represser, and the other is that VDR physically interacts with other factors that regulate renin transcription via cyclic AMP response element (CRE) in renin gene promoter. The third Aim is to explore the potential of vitamin D analogs as renin inhibitors and anti- hypertensive agents. Our discovery of vitamin D as a potent negative endocrine regulator of the RAS provides a molecular basis to explore the potential of vitamin D analogs as renin inhibitors for therapeutic purposes. We have identified a group of low calcemic vitamin D analogs that can effectively suppress renin biosynthesis and plasma renin activity in cell cultures and in mice. We will further test the efficacy of these analogs to reduce renin production and to lower blood pressure in high-renin hypertensive animal models such as the Goldblatt hypertensive rats and spontaneously hypertensive rats. These studies will further enhance our understanding of the novel physiology of the vitamin D endocrine system and its pharmacological applications in the regulation of the RAS and cardiovascular system.

描述（由申请人提供）：累积的临床和实验证据支持维生素D内分泌系统在心血管功能调节中的重要作用。例如，维生素D治疗已被证明可显著降低血液透析患者的心血管死亡风险。肾素-血管紧张素系统（RAS）在维持电解质、细胞外容量和血压稳态中起核心作用; RAS的过度激活已被公知会引起心血管问题，如高血压、心脏肥大和动脉粥样硬化。近年来，我们获得了大量的证据表明维生素D通过抑制肾素的生物合成来调节RAS。我们发现，破坏小鼠体内的维生素D信号导致RAS激活，导致高血压和心脏肥大，并且1，25-二羟维生素D3通过VDR依赖性机制直接抑制肾素基因转录。在本申请中，我们将继续探索维生素D对RAS的生理和药理作用，提出三个具体目标。第一个目的是通过转基因方法进一步确定维生素D和甲状旁腺激素（PTH）在体内RAS调节中的作用。我们将研究在产生肾素的JG细胞中过表达人（h）VDR的转基因（Tg）小鼠以及仅在JG细胞中表达hVDR转基因（VDRKO-hVDR）的VDR敲除（KO）小鼠。对野生型、VDRKO、Tg-hVDR和VDRKO-hVDR小鼠的平行分析将使我们能够进一步阐明维生素D和PTH在调节肾素基因表达中的体内作用。第二个目的是阐明维生素D调节肾素基因表达的分子机制。基于我们现有的证据，我们将重点探讨两个间接机制：一是维生素D通过刺激其他转录抑制因子抑制肾素表达，另一个是VDR通过肾素基因启动子中的环AMP反应元件（CRE）与其他调节肾素转录的因子发生物理相互作用。第三个目的是探索维生素D类似物作为肾素抑制剂和抗高血压药物的潜力。我们发现维生素D是RAS的一种有效的负性内分泌调节剂，这为探索维生素D类似物作为治疗目的的肾素抑制剂的潜力提供了分子基础。我们已经鉴定了一组低钙维生素D类似物，其可以有效地抑制细胞培养物和小鼠中的肾素生物合成和血浆肾素活性。我们将进一步测试这些类似物在高肾素高血压动物模型如Goldblatt高血压大鼠和自发性高血压大鼠中减少肾素产生和降低血压的功效。这些研究将进一步增强我们对维生素D内分泌系统的新生理学及其在RAS和心血管系统调节中的药理学应用的理解。