Tension-induced SGK-1 Signaling in AAA

AAA 中张力诱导的 SGK-1 信号转导

• 批准号: 10604248
• 负责人: Jean Marie Ruddy
• 金额: $ 17.65万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-14 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10604248
• 关键词: Abdominal Aortic Aneurysm; Affect; American; Aneurysm; Angiotensin II; Aorta; Aortic Aneurysm; Atherosclerosis; Attenuated; Automobile Driving; Biochemical; Biomechanics; Blood Pressure; Bone Marrow Examination; CCL2 gene; Cardiovascular system; Cell Culture Techniques; Cell Line; Cell Membrane Permeability; Cells; Critical Thinking; Culture Media; Dependence; Development; Diameter; Disease; Enzyme-Linked Immunosorbent Assay; Epidemiology; Experimental Designs; Exposure to; Flow Cytometry; Future; Gelatinase B; Glucocorticoids; Growth; Harvest; Hyperplasia; Hypertension; ITGAM gene; In Vitro; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Infusion procedures; Innovative Therapy; Interleukin-6; Knock-out; Knockout Mice; Laboratories; Laboratory Research; Life; Link; Macrophage; Mechanics; Mediating; Mentorship; Microscopy; Modeling; Molecular; Mouse Strains; Mus; Pathology; Pathway interactions; Patients; Peptide Hydrolases; Peptides; Pharmacotherapy; Phosphotransferases; Plasma; Play; Population; Procedures; Production; Protein Secretion; Pulmonary Hypertension; Regulation; Research Methodology; Research Personnel; Resources; Role; Rupture; Serum; Signal Transduction; Small Interfering RNA; Smooth Muscle Myocytes; Stains; Stimulus; Stretching; Stroke; Tissues; Unstable angina; Vascular Diseases; Vascular Smooth Muscle; Vascular remodeling; Western Blotting; Wild Type Mouse; Work; abdominal aorta; blood pressure elevation; cardiovascular risk factor; career; cytokine; digital measure; hypertensive; in vivo; inhibitor; inhibitor therapy; migration; monocyte; mortality; mortality risk; mouse model; new therapeutic target; response; skills; transcription factor; vascular inflammation

Hypertension (HTN) is a major risk factor for cardiovascular mortality and greater than 30% of Americans are currently affected. The impact of elevated blood pressure on aortic wall remodeling has significant implications for vascular disease in general, and aneurysm formation specifically. AngiotensinII (AngII) is a potent vasoactive peptide and contributes to vascular inflammation by stimulating production of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) to augment the population of macrophages within the aortic wall. Interestingly, patients with abdominal aortic aneurysms (AAA) have also consistently demonstrated elevated plasma and aortic tissue levels of IL-6, along with dense macrophage infiltration. Defining the tension-induced kinase driving cytokine production is vital to identifying a potential target for pharmacotherapy of AAA. Recent evidence has identified serum and glucocorticoid inducible kinase-1 (SGK-1) as a mechanically sensitive kinase that contributes to intimal hyperplasia, atherosclerosis, and pulmonary hypertension, and its downstream regulation of several transcription factors can modulate the production of IL-6 and MCP-1. Therefore, it is hypothesized that HTN promotes VSMC activation of SGK-1 to produce pro-inflammatory cytokines that accumulate macrophages to propagate AAA growth. The first specific aim will analyze tension-induced SGK-1 activation and cytokine expression from aortic VSMCs harvested from C57Bl/6 wild-type and SGK-1 knockout (SGK-1KO) mice. The ability of this conditioned media to stimulate monocyte/macrophage migration through a permeable membrane will also be assessed. In the second aim, C57Bl/6 and SGK-1KO mice with induced HTN (via AngII infusion) will be evaluated for the activation of SGK-1, production of pro-inflammatory cytokines IL-6 and MCP-1, and accumulation of macrophages. Dependence of this inflammatory response on SGK-1 activity will be further explored by treating wild-type mice subjected to induced HTN with the selective SGK-1 inhibitor EMD638683. The third specific aim will focus on the role of SGK-1 in initiating and propagating AAA formation by employing a validated model of AAA induction with CaCl2 application and treating mice with EMD638683. The terminal procedure will evaluate AAA diameter and production of target cytokines and proteases. The opportunity for elevated tension to augment this effect will be explored by inducing HTN and concurrent AAA in the two mouse strains and conducting parallel biochemical analysis. By establishing this link between HTN, inflammation, and the initiation of degradative vascular remodeling through the activity of SGK-1, future studies may utilize targeted inhibitor therapies to attenuate aneurysmal degeneration in the abdominal aorta. Moreover, the experimentation outlined in this project will provide an opportunity for Dr. Ruddy to engage the resources of MUSC and the Cardiovascular Research Laboratory to expand her research methodology, develop mentorship qualities, enhance her critical-thinking skills, and augment her grantsmanship to propel her toward a career as an independent researcher.

高血压（HTN）是心血管死亡的主要危险因素，超过30%的美国人

项目成果

Discharge to a Post-Acute Care Facility after Emergent Femoral Artery Repair is Not Protective Against Wound Complications.

紧急股动脉修复术后出院至急性后护理机构并不能预防伤口并发症。

• DOI: 10.1016/j.avsg.2019.12.032
• 发表时间: 2020
• 期刊: Annals of vascular surgery
• 影响因子: 1.5
• 作者: Anderson,Joseph;King,Ryan;Brothers,Thomas;Robison,Jacob;Veeraswamy,Ravi;Wooster,Mathew;Mukherjee,Rupak;Ruddy,JeanMarie
• 通讯作者: Ruddy,JeanMarie

Hostile neck anatomy contributes to higher rates of reintervention following endovascular aortic repair for ruptured infrarenal abdominal aortic aneurysm.

敌对的颈部解剖结构有助于对肾下腹主动脉瘤破裂进行血管内主动脉修复术后的再干预率更高。

• DOI: 10.1177/17085381241239428
• 发表时间: 2024
• 期刊: Vascular
• 影响因子: 1.1
• 作者: Gedney,Ryan;Barksdale,Christian;Wright,AntwanaSharee;Genovese,ElizabethA;Ruddy,JeanMarie
• 通讯作者: Ruddy,JeanMarie

Elevated Cardiopulmonary Complications after Revascularization in Patients with Severe Mental Health Disorders.

• DOI: 10.33425/2639-8486.1122
• 发表时间: 2021
• 期刊: Cardiology & vascular research (Wilmington, Del.)
• 作者: Gober, Leah;Brown, Adam;Bunnell, Avianne P;Bunnell, Brian E;Ruddy, Jean Marie
• 通讯作者: Ruddy, Jean Marie

Racial and Gender Disparity in Achieving Optimal Medical Therapy for Inpatients with Peripheral Artery Disease.

• 发表时间: 2020
• 期刊: Annals of vascular medicine and research
• 作者: Gober L;Bui A;Ruddy JM
• 通讯作者: Ruddy JM

Response by Sex in Patient-Centered Outcomes With Baroreflex Activation Therapy in Systolic Heart Failure.

• DOI: 10.1016/j.jchf.2021.01.012
• 发表时间: 2021-06
• 期刊: JACC. Heart failure
• 作者: Lindenfeld J;Gupta R;Grazette L;Ruddy JM;Tsao L;Galle E;Rogers T;Sears S;Zannad F
• 通讯作者: Zannad F