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.

Public Health Relevance

High blood pressure is a morbid condition affecting greater than 30% of the American population, and inadequate control is associated with unstable angina, cerebrovascular accidents, and presence of aortic aneurysms. Abdominal aortic aneurysms (AAA) can be particularly concerning since they often go unnoticed until very large and carry a significant risk of mortality with rupture. This project will investigate how the abdominal aorta responds to changes in blood pressure to elaborate inflammatory mediators and initiate macrophage accumulation to propagate AAA formation, thereby identifying a molecular pathway to target for innovative therapy to attenuate aortic dilation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08HL143169-01A1
Application #
9742633
Study Section
NHLBI Mentored Clinical and Basic Science Review Committee (MCBS)
Program Officer
Huang, Li-Shin
Project Start
2019-04-14
Project End
2024-03-31
Budget Start
2019-04-14
Budget End
2020-03-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Medical University of South Carolina
Department
Surgery
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29407