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“Mechanisms of Calcification in Atherosclerosis: Role of Macrophages and the Transient Receptor Potential Canonical 3 (TRPC3) Channel”

Dube, Prabhatchandra R
http://rave.ohiolink.edu/etdc/view?acc_num=mco1512574541600974

Abstract Details

2017, Doctor of Philosophy (PhD), University of Toledo, Biomedical Sciences (Molecular Medicine).
Atherosclerosis is the main cause of coronary and carotid artery disease causing highest number of deaths in the world due to cardiovascular disease. Calcification is a frequent complication associated with atherosclerotic plaques and contributing factor to their instability and rupture. Mechanisms of vascular calcification exert the similar complexity as that of bone formation and involve participation of bone related proteins and factors such as bone morphogenetic protein-2 (BMP-2) and Runt related transcription factor-2 (Runx-2) among others. Vascular calcification is an intricate process involving a cross talk between vascular smooth muscle cells, endothelium and macrophages. Although vascular smooth muscle cells are attributed as key culprits in the process of calcification, recent studies also point to the important role of endothelium and macrophages. Macrophages contribute to vascular ossification by releasing cytokines like TNF- a and IL-6 that can induce osteogenic transformation and mineralization of vascular smooth muscle cells, and also becoming themselves osteoclast-like cells. Macrophages present in both human and murine atherosclerotic lesions are diverse in nature, with the M1 or inflammatory, and the M2 or anti-inflammatory macrophage subtypes dominating throughout the lesion development process. However, the osteogenic potential of M1 and M2 macrophages remains undetermined. Macrophages in the lesions undergo apoptosis and affect the plaque development process. Macrophage apoptosis is also a known cause of calcification. ER stress has emerged as the chief mechanism causing macrophage apoptosis in the atherosclerotic lesions. Recent studies from our lab have shown that in macrophages Transient Receptor Potential Canonical 3 (TRPC3) channel contributes to ER stress-induced apoptosis in M1, but not in M2 macrophages. TRPC3 is a non-selective Ca2+-permeable cation channel belonging to TRPC family and larger TRP superfamily of cation channels exhibiting both receptor dependent and significant constitutive functions. Based on a strong relationship between ER stress and vascular calcification we desired to examine whether TRPC3 would play a role in the osteogenic signaling of polarized macrophages in vitro. Our findings reveal that a constitutive BMP-2 dependent process operates in M1 macrophages that is not affected by TRPC3 or ER stress. Importantly, these findings suggest the existence of a mechanism in M1 macrophages by which secretion of BMP-2 results in autocrine and/or paracrine action that maintains constitutive activation of BMP-2 receptor/ SMAD1/5 signaling axis in these cells. Due to presence of this robust constitutive BMP-2 dependent osteogenic signaling the real impact of macrophage TRPC3 could not be elucidated. Hence we used in vivo approach to examine the effect of macrophage Trpc3 on osteogenic signaling and calcification in advanced atherosclerotic plaques. We used low density lipoprotein receptor knockout (Ldlr -/-) mice with macrophage specific deletion of Trpc3 (MacTrpc3-/-/Ldlr-/-) on high fat diet for 25 weeks to induce calcification of advanced atherosclerotic lesions. Our studies indicate that in the advanced atherosclerotic setting TRPC3 is a mandatory component of a macrophage related, BMP-2 –dependent mechanism that regulates calcification of atherosclerotic plaques. These findings also divulge a novel aspect of macrophage function in the setting of vascular calcification.
Guillermo Vazquez (Advisor)
Viviana Ferreira (Committee Member)
David Giovannucci (Committee Member)
Jennifer Hill (Committee Member)
Sivarajan Kumarasamy (Committee Member)
Beata Lecka-Czernik (Committee Member)
Biomedical Research

Recommended Citations

Citations

  • Dube, P. R. (2017). “Mechanisms of Calcification in Atherosclerosis: Role of Macrophages and the Transient Receptor Potential Canonical 3 (TRPC3) Channel” [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1512574541600974

    APA Style (7th edition)

  • Dube, Prabhatchandra. “Mechanisms of Calcification in Atherosclerosis: Role of Macrophages and the Transient Receptor Potential Canonical 3 (TRPC3) Channel”. 2017. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1512574541600974.

    MLA Style (8th edition)

  • Dube, Prabhatchandra. "“Mechanisms of Calcification in Atherosclerosis: Role of Macrophages and the Transient Receptor Potential Canonical 3 (TRPC3) Channel”." Doctoral dissertation, University of Toledo, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=mco1512574541600974

    Chicago Manual of Style (17th edition)

mco1512574541600974
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This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.