Novel mechanisms of arterial contractility regulation by statins

他汀类药物调节动脉收缩力的新机制

• 批准号: 10292097
• 负责人: Raquibul Hasan
• 金额: $ 42.45万
• 依托单位: MERCER UNIVERSITY MACON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292097
• 关键词: Aorta; Arteries; Atherosclerosis; Biochemical; Biological Assay; Biotinylation; Blood Circulation; Blood Vessels; Blood flow; Caliber; Cardiovascular system; Cell surface; Cholesterol; Clinical; Contractile System; Coronary Arteriosclerosis; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Data; Data Analyses; Diffuse; Drug Prescriptions; Education; Egtazic Acid; Endothelium; Exposure to; Female; Fluorescence; Formulation; Future; Geometry; Goals; Guanylate Cyclase; Image; Immunofluorescence Immunologic; In Vitro; Infrastructure; Ion Channel; Knowledge; L Cells; Laboratories; Lipids; Measurement; Measures; Mediating; Mesenteric Arteries; Molecular; Molecular Target; Muscle Cells; Myography; NOS3 gene; Nimodipine; Nitric Oxide; Organ; Perfusion; Pharmaceutical Preparations; Pharmacy Students; Pharmacy facility; Phenotype; Phenylephrine; Physiological; Pravastatin; Prevention; Process; Proteins; Rattus; Regulation; Relaxation; Reporting; Research; Resistance; Rest; Role; Ryanodine; Sarcoplasmic Reticulum; Scientist; Signal Transduction; Simvastatin; Small Interfering RNA; Smooth Muscle Myocytes; Solid; Sprague-Dawley Rats; Stroke; Systemic blood pressure; Techniques; Testing; Thapsigargin; Therapeutic; Therapeutic Effect; Universities; Vasodilation; Western Blotting; atorvastatin; base; cGMP production; cerebral artery; clinically significant; college; extracellular; graduate student; imaging genetics; in silico; inhibitor/antagonist; knock-down; male; middle cerebral artery; molecular imaging; myosin phosphatase; nanomolar; novel; pharmacy benefit; phosphoric diester hydrolase; pressure; protein expression; receptor; rosuvastatin; screening; sildenafil; vasoconstriction; voltage; volunteer

PROJECT SUMMARY/ABSTRACT: Statins are cholesterol-lowering drugs that have been clinically used for more than 30 years for the prevention and treatment of atherosclerotic cardiovascular diseases including coronary artery disease and stroke. The conventional view is that the vascular effects of statins are cholesterol lowering-dependent and/or -independent (or pleiotropic), both of which require long-term treatment. Surprisingly, studies to precisely determine direct vascular effects of statins are lacking and their clinical significance obscure, because almost all studies that reported vascular effects of statins were conducted a) using supratherapeutic concentrations (1000-fold or higher) of the drug, b) mostly on non-resistance, conduit arteries that do not control regional organ blood flow and systemic blood pressure, and c) on cultured arteries and smooth muscle cells that may have undergone transformation from a contractile to a non-contractile, proliferative phenotype. Our long-term goal is to understand direct arterial contractility regulation by therapeutic concentrations of statins on fresh isolated arteries and isolated myocytes. The rationale behind the proposed research is that the gained knowledge will be critical for enhancing our understanding of vascular actions of statins and future formulation of more effective, safer and personalized statin therapy. The objective of this application is to understand molecular mechanisms of direct statin effects on different vasculatures. Our novel preliminary data obtained using an integrated approach suggests that therapeutic concentrations (0.1-10nM) of statins produce both vasoconstriction and vasodilation depending on vascular microenvironment. Importantly, we found that such vascular effects occur at nanomolar concentrations, within 2-3 minutes of drug application and are independent of lipid synthesis inhibition by statins, suggesting cell-surface channel or receptor based mechanisms. Indeed, our data shows that statin-mediated vasoconstriction is dependent on smooth muscle cell L-type Ca2+ channel opening and Ca2+ influx, whereas vasorelaxation is consistent with cGMP-based phosphodiesterase (PDE) inhibition. The central hypothesis of this proposal is that statins have diverse vascular effects that are, at least, mediated by the activation of voltage-gated CaV1.2 ion channel and extracellular Ca2+ influx into arterial smooth muscle cells to cause vasocontraction, and inhibition of cGMP-dependent PDE in smooth muscle cells leading to vasodilation. The objective of the proposed research will be achieved using a combination of biochemical, molecular, imaging, genetic, in-vitro, in-silico and functional approaches. With a collaborative team of three prominent scientists, the proposed project will greatly enhance our understanding of novel vascular actions of the world’s most prescribed class of lipid-lowering medications. Our proposed activity will also establish infrastructure for cardiovascular research and education at the Mercer University College of Pharmacy, and will greatly benefit Pharmacy students, graduate students and volunteers through knowledge creation and exposure to a broad spectrum of laboratory and data analysis techniques.

项目摘要/摘要： 他汀类药物是临床上使用了30多年的降胆固醇药物，用于预防和治疗高血压 治疗动脉粥样硬化性心血管疾病，包括冠状动脉疾病和中风。传统观点 他汀类药物的血管效应是降胆固醇依赖的和/或非依赖的(或多效性的)，两者都是 需要长期治疗。令人惊讶的是，精确确定他汀类药物直接血管效应的研究是 缺乏其临床意义，因为几乎所有报道他汀类药物血管效应的研究都是 A)使用超治疗浓度(1000倍或更高)的药物，b)主要针对非耐药的管道 不控制局部器官血流和全身血压的动脉，以及c)培养的动脉和光滑的动脉 肌肉细胞可能经历了从收缩表型到非收缩、增殖表型的转变。我们的 长期目标是了解治疗浓度的他汀类药物对新鲜血液的直接动脉收缩调节作用 分离的动脉和分离的心肌细胞。这项拟议研究背后的理由是，所获得的知识将是 对于增进我们对他汀类药物血管作用的了解以及未来制定更有效、更安全和更有效的 个性化的他汀类药物治疗。本应用的目的是了解直接他汀类药物的分子机制。 对不同血管的影响。我们使用综合方法获得的新的初步数据表明 治疗浓度(0.1-10 nm)的他汀类药物可同时产生血管收缩和血管扩张，具体取决于血管 微环境。重要的是，我们发现这种血管效应发生在纳摩尔浓度，在2-3 药物应用分钟，不依赖于他汀类药物对脂质合成的抑制，提示细胞表面通道或 基于受体的机制。事实上，我们的数据表明，他汀类药物介导的血管收缩依赖于平滑肌 细胞L型钙通道开放和钙内流，而血管松弛与cGMP的作用一致 磷酸二酯酶(PDE)抑制。这一提议的中心假设是他汀类药物有不同的血管 至少由电压门控CaV1.2离子通道和细胞外钙离子激活所介导的效应 血管内流引起血管收缩，并抑制cGMP依赖的PDE 导致血管扩张的平滑肌细胞。拟议研究的目标将通过使用 结合了生化、分子、成像、遗传、体外、体内和功能方法。使用一个 由三位杰出科学家组成的合作团队，提出的项目将极大地提高我们对小说的理解 世界上处方最多的降脂药物的血管作用。我们提议的活动还将 在美世大学药学院建立心血管研究和教育基础设施，并将 通过知识创造和接触广泛的知识，使药学学生、研究生和志愿者受益匪浅 实验室和数据分析技术的范围。