Atherosclerosis is the main cause of coronary and carotid artery disease and a leading cause of morbidity/mortality in the United States. Ischemic symptoms due to advanced stenosis or thromboembolic events that follow plaque rupture are major clinical manifestations of the disease. Efforts in the field are aimed at reducing plaque progression, improve stability of advanced plaques or stimulate plaque regression. The particular impact that macrophage apoptosis and migration have in advanced lesions is subject of intensive research efforts. Yet, their potential applicability to human pathology is still under debate. Definitions can be achieved by acknowledging the distinctive impact of macrophage diversity in plaque composition and fate, and by exploring molecular components that may selectively affect a macrophage type and not others. The long term goal of this proposal is to examine the contribution of macrophage Transient Receptor Potential Canonical 3 (TRPC3) to these mechanisms in the context of atherosclerosis. In recent work we showed that advanced plaques in ApoE knockout mice with bone marrow deletion of TRPC3 have less necrosis and macrophage apoptosis than controls, and bone marrow derived macrophages from mice with macrophage-specific deletion of TRPC3 (MacTRPC3KO) and differentiated in vitro to the M1 type, have reduced ER stress-induced apoptosis. Remarkably, M2 macrophages were not affected. Our preliminary studies in MacTRPC3KOApoEKO mice show that, compared to controls, advanced plaques have reduced macrophage content and that TRPC3 deletion promotes a reduction in M1/M2 ratios, and decreased apoptosis. We have also found that TRPC3 deficient M1, but not M2 macrophages, have augmented in vitro migration. The general hypothesis is that by virtue of its roles in mechanisms associated to apoptosis and migration of M1 macrophages TRPC3 can exert profound effects on the characteristics of plaque composition and integrity. It is anticipated that suppression of macrophage TRPC3 in vivo will lessen cellularity and necrosis of advanced plaques and favor regressive conditions.
In specific aim 1 we will examine the impact of TRPC3 expression and constitutive function on inflammatory signaling and migration of polarized macrophages under conditions of ER stress.
In specific aim 2 we will study the impact of macrophage-specific loss or gain of TRPC3 function on the characteristics of atherosclerotic lesions in a mouse model of the disease.
In specific aim 3 we will examine the impact of macrophage-specific loss or gain of TRPC3 function on macrophage migration and plaque regression in mouse models of the disease.
Atherosclerosis is the major cause of coronary and carotid artery disease and constitutes a leading cause of morbidity/mortality in western societies. This proposal examines the role of Transient Receptor Potential Canonical 3 channel (TRPC3) in mechanisms associated to apoptosis, inflammation and migration of inflammatory M1 macrophages in atherosclerotic plaques by examining the impact of genetic manipulation of macrophage TRPC3 expression on the composition, stability and regression of advanced plaques. The information obtained may lead to identification of TRPC3 as a novel therapeutic target to manipulate lesional macrophages in a phenotype selective manner as an alternative strategy to improve plaque stability and/or regression and reduce the incidence of clinical events.
| Dube, Prabhatchandra R; Chikkamenahalli, Lakshmikanth L; Birnbaumer, Lutz et al. (2018) Reduced calcification and osteogenic features in advanced atherosclerotic plaques of mice with macrophage-specific loss of TRPC3. Atherosclerosis 270:199-204 |
| Dube, Prabhatchandra R; Birnbaumer, Lutz; Vazquez, Guillermo (2017) Evidence for constitutive bone morphogenetic protein-2 secretion by M1 macrophages: Constitutive auto/paracrine osteogenic signaling by BMP-2 in M1 macrophages. Biochem Biophys Res Commun 491:154-158 |
| Kumarasamy, Sivarajan; Solanki, Sumeet; Atolagbe, Oluwatomisin T et al. (2017) Deep Transcriptomic Profiling of M1 Macrophages Lacking Trpc3. Sci Rep 7:39867 |
| Solanki, Sumeet; Dube, Prabhatchandra R; Birnbaumer, Lutz et al. (2017) Reduced Necrosis and Content of Apoptotic M1 Macrophages in Advanced Atherosclerotic Plaques of Mice With Macrophage-Specific Loss of Trpc3. Sci Rep 7:42526 |
