Wednesday, April 2, 2025
4/2/2025
RECK as a Therapeutic Target for Atherosclerosis - PROJECT SUMMARY Despite significant progress in diagnostic and therapeutic strategies and the promotion of a healthy lifestyle, cardiovascular diseases (CVD), including atherosclerotic coronary heart disease (CHD), remain the primary cause of morbidity and mortality in the United States. Our long-term goal is to identify new targets for therapeutic invention to limit the development and progression of CHD. Our immediate goal is to determine whether the induction of RECK (Reversion Inducing Cysteine Rich Protein with Kazal Motifs) is a novel therapeutic to prevent the development and progression of atherosclerosis. RECK, a regulator of proteinases, is expressed in vascular smooth muscle cells (SMC) and macrophages (Mφ), two major cell types involved in atherosclerosis. However, the biological functions of RECK in atherosclerosis remain largely unknown. We and others have reported that RECK inhibits the activation of matrix metalloproteinases. Our preliminary data suggest that RECK in SMCs attenuates inflammatory responses and pro-inflammatory SMC phenotype modulation while inhibiting extracellular protein degradation. In Mφ, RECK promotes clearance of dying cells via efferocytosis and attenuation of inflammatory responses. Based on these novel preliminary data, we hypothesize that RECK induction impedes atherosclerosis by inhibiting inflammation and tissue degeneration while promoting efferocytosis. Aim 1 will determine if RECK overexpression in SMC-like cells attenuates atheroprogression and promotes a stable atherosclerotic plaque phenotype via inhibiting inflammatory responses and tissue remodeling/degradation. We have generated tamoxifen-inducible SMC-RECK overexpressor mice on Apoe-/- background. RECK will be induced as a therapeutic strategy after the animals develop atherosclerosis. Primary endpoints include atherosclerotic burden and plaque stability. Single cell RNA sequencing (scRNASeq) analyses and lineage tracing will help identify cell types and intercellular interactions mediated by RECK induction. The molecular mechanisms regulated by increased RECK will be analyzed in primary SMCs. Aim 2 will study if RECK overexpression in Mφ-like cells attenuates atheroprogression by enhancing efferocytosis and suppressing proinflammatory signaling. We have generated tamoxifen-inducible Mφ-RECK overexpressor mice. As a therapeutic strategy, RECK is induced after the animals develop atherosclerosis. Primary endpoints will be atherosclerotic burden, plaque stability, efferocytosis, inflammation, and scRNASeq/transcriptome analyses. Aim 3 will investigate if systemic RECK overexpression attenuates atherosclerosis progression, aiming to prove RECK as an anti-atherosclerosis agent. Completing these genetic and proof-of-concept interventional approaches will demonstrate that RECK induction is atheroprotective.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).