Cell-specific role and therapeutic potential of KCa3.1 in atherosclerosis

KCa3.1 在动脉粥样硬化中的细胞特异性作用和治疗潜力

• 批准号: 10436073
• 负责人: DOUGLAS K BOWLES
• 金额: $ 55.27万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10436073
• 关键词: Angiography; Animal Model; Apolipoprotein E; Area; Arterial Fatty Streak; Atherosclerosis; Benign; Calcium-Activated Potassium Channel; Cause of Death; Cells; Cessation of life; Characteristics; Clinical; Clinical Trials; Coagulation Process; Collagen; Complex; Coronary; Coronary Angiography; Coronary Arteriosclerosis; Coronary heart disease; Development; Disease Progression; Disease model; Drug Targeting; FDA approved; Family suidae; Foam Cells; Foundations; Gene Expression; Genes; Genetic; Goals; Heart Diseases; Histology; Hospitals; Human; Immunohistochemistry; In Vitro; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Knockout Mice; Lesion; Link; Mammals; Medial; Mediating; Mediator of activation protein; Modeling; Mus; Myocardial Infarction; Necrosis; Outcome; Pathogenesis; Pharmaceutical Preparations; Pharmacology; Phenotype; Play; Regulator Genes; Reporter; Role; Rupture; Set protein; Signal Transduction; Smooth Muscle; Solid; Stroke; Symptoms; Testing; Therapeutic; Tomatoes; Translating; United States; acute coronary syndrome; cell type; combat; coronary lesion; coronary plaque; cost; drug testing; in vivo; inhibitor; macrophage; migration; myocardin; next generation; novel; porcine model; pre-clinical; recruit; therapeutically effective; tool; transcription factor REST; transcriptome sequencing; transdifferentiation; translational potential; ultrasound

Pathogenesis of coronary artery disease is complex, with multiple cell types contributing to lesion size and composition. Acute coronary syndromes are most often associated with rupture of complex, vulnerable plaques that are otherwise clinically benign. The progression to either a relatively benign, stable lesion or a rupture-prone, vulnerable plaque has been linked to key lesion characteristics, i.e. smooth muscle (SM) and collagen content, macrophage infiltration and necrotic core area within the lesion. The objectives of this proposal are to 1) determine the SM-specific role and underlying mechanism(s) by which the intermediate conductance, Ca2+-activated K+ channel, KCa3.1 (encoded by Kcnn4), dictates atherosclerotic lesion formation and composition and 2) determine the translational potential of clinically approved KCa3.1 inhibitors on lesion development in a large mammal model of coronary artery disease (CAD). In support, we provide the first genetic evidence of a causal link between KCa3.1 and lesion size and SM and macrophage recruitment. The overall hypothesis is that KCa3.1 activation increases migration of SM and macrophages into the intima and contributes to lesion formation. Conversely, blocking KCa3.1, both by genetic silencing or pharmacologically, will decrease atherosclerotic lesion size and beneficially alter composition. Aim 1 will determine the contribution of KCa3.1 in smooth muscle to atherosclerotic lesion formation and composition. Specifically, we will use SM-specific, inducible KO mice to examine the role of KCa3.1 in determining plaque size, composition and gene expression. Aim 2 will define both upstream (REST) and downstream (DOCK2) mechanisms determining KCa3.1 effects on SM and atherosclerosis. We will use genetically modified mice to examine the role of REST and DOCK2 in mediating SM effects of KCa3.1 on phenotype, proliferation, migration, plaque size and composition. In addition, we will use RNA sequencing to identify novel mechanisms of atherosclerosis development by KCa3.1. We will use VSM lineage-tracking in Aim 3 will use SM lineage-tracking to determine role of SMC-KCa3.1 in mediating SMC intimal to medial migration and foam cell transdifferentiation during atherosclerotic lesion development. Finally, Aim 4 will determine the effect of the FDA approved KCa3.1 inhibitor, senicapoc, on atherosclerosis development in a swine model of CAD. We longitudinally track coronary artery disease progression using angiography and IVUS in familial hypercholesterolemic (FH) swine to test the ability of KCa3.1 inhibition with senicapoc, to decrease the size and promote a more favorable composition of coronary lesions. The long-term goal is to provide the pre-clinical foundation for translating current therapeutic tools and developing the next generation drugs targeting KCa3.1 and/or downstream signaling to beneficially manipulate atherosclerotic lesion composition.

冠状动脉疾病的发病机制是复杂的，多种细胞类型决定了病变的大小