Bone marrow deficiency of TRPC3 channel reduces early lesion burden and necrotic core of advanced plaques in a mouse model of atherosclerosis

Tano, Jean-Yves; Solanki, Sumeet; Lee, Robert H.; Smedlund, Kathryn; Birnbaumer, Lutz; Vázquez, Guillermo

doi:10.1093/cvr/cvt231

Cited by 44 publications

(81 citation statements)

References 27 publications

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“…Lungs have a high content of endothelial cells, facilitating immunoblot detection of HA-tagged TRPC3 of endothelial origin. Contrarily to what is observed with other endothelial promoters (e.g., Tie2, Ve-cadherin), there was no expression of TRPC3-HA in bone marrow-derived macrophages from TgEST3ApoEKO mice, which is of importance as we recently showed that macrophage TRPC3 influences the characteristics of early and advanced atherosclerotic lesions of ApoeKO mice by virtue of its role in mechanisms associated to macrophage apoptosis (11,15). Immunohistochemistry for HA epitope in aortic root sections from the transgenic mice confirmed endothelial localization of TRPC3-HA (Fig.…”

Section: Resultssupporting

confidence: 48%

“…Endothelial inflammatory signaling, monocyte recruitment, and the balance between survival and apoptosis of lesional macrophages, are all fundamental in initiation and progression of atherosclerotic lesions as well as in determining the fate of the plaque at advanced stages (9,10). A paramount piece of experimental evidence supporting a role of TRPC3 in atherogenesis was provided by our recent findings in a mouse model of atherosclerosis demonstrating that TRPC3 contributes to mechanisms underlying necrotic core growth in advanced atherosclerotic plaques of Apoe knockout (ApoeKO) mice by influencing the rate of apoptosis of lesional macrophages (11). However, the expression of TRPC3 is ubiquitous and macrophages are not the sole atherorelevant cells where this channel is present.…”

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confidence: 99%

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Increased size and cellularity of advanced atherosclerotic lesions in mice with endothelial overexpression of the human TRPC3 channel

Smedlund

Birnbaumer

Vázquez

2015

Proc. Natl. Acad. Sci. U.S.A.

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In previous in vitro studies, we showed that Transient Receptor Potential Canonical 3 (TRPC3), a calcium-permeable, nonselective cation channel endowed with high constitutive function, is an obligatory component of the inflammatory signaling that controls expression of the vascular cell adhesion molecule-1 (VCAM-1) and monocyte adhesion to coronary artery endothelial cells. Also, TRPC3 expression in these cells was found to be up-regulated by proatherogenic factors, which enhanced inflammation and VCAM-1 expression. However, it remained to be determined whether these in vitro findings were of relevance to atherosclerotic lesion development in vivo. To answer this important question in the present work, we generated mice with endothelial-specific overexpression of human TRPC3 in an Apoe knockout background (TgEST3ApoeKO) and examined lesions in the aortic sinus following 10 and 16 wk on a high-fat diet. No significant differences were found in size or complexity of early stage lesions (10 wk). However, advanced plaques (16 wk) from TgEST3ApoeKO mice exhibited a significant increase in size and macrophage content compared with nontransgenic littermate controls. Remarkably, this change was correlated with increased VCAM-1 and phospho-IkBα immunoreactivity along the endothelial lining of lesions from transgenic animals compared with controls. These findings validate the in vivo relevance of previous in vitro findings and represent, to our knowledge, the first in vivo evidence for a proatherogenic role of endothelial TRPC3.TRPC3 channels | atherosclerosis | endothelial inflammation

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Section: Resultssupporting

confidence: 48%

mentioning

confidence: 99%

Increased size and cellularity of advanced atherosclerotic lesions in mice with endothelial overexpression of the human TRPC3 channel

Smedlund

Birnbaumer

Vázquez

2015

Proc. Natl. Acad. Sci. U.S.A.

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“…In ApoE-deficient mice transplanted with the bone marrow of TRPC3-null animals and kept on a high-fat diet, atherosclerotic plaques occurred later and were smaller with a reduced necrotic core compared with control subjects (Tano et al, 2014).…”

Section: Transient Receptor Potential Channels In Cardiovascular Dmentioning

confidence: 94%

“…There is preliminary evidence to implicate TRPC3 in efferocytosis ("burying the dead cells"). Bone marrow-derived macrophages obtained from TRPC3(2/2) mice showed decreased survival and impaired efferocytosis (Tano et al, 2011(Tano et al, , 2014. If so, TRPC3 may play an important role not only in disease initiation (endothelial damage) but also in disease progression (see Tano et al, 2012).…”

Section: Transient Receptor Potential Channels In Cardiovascular Dmentioning

confidence: 99%

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

2014

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“…Solanki et al [81] shown that the number of ERS-related apoptotic macrophages was increased by a deficiency of calcium-permeable channel transient receptor potential canonical 3 (TRPC3). TRPC3 reduced scavenging of apoptotic SMCs and macrophages and then allowed cells to undergo secondary necrosis, thereby increasing the thrombogenicity of the plaque [82] . Suppression of ERS decreased the number of apoptotic macrophages [83] .…”

Section: Endoplasmic Reticulum Stress Regulates Cardiovascular Physiomentioning

confidence: 99%

Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases

2016

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Endoplasmic reticulum is a principal organelle responsible for folding, post-translational modifications and transport of secretory, luminal and membrane proteins, thus palys an important rale in maintaining cellular homeostasis. Endoplasmic reticulum stress (ERS) is a condition that is accelerated by accumulation of unfolded/misfolded proteins after endoplasmic reticulum environment disturbance, triggered by a variety of physiological and pathological factors, such as nutrient deprivation, altered glycosylation, calcium depletion, oxidative stress, DNA damage and energy disturbance, etc. ERS may initiate the unfolded protein response (UPR) to restore cellular homeostasis or lead to apoptosis. Numerous studies have clarified the link between ERS and cardiovascular diseases. This review focuses on ERS-associated molecular mechanisms that participate in physiological and pathophysiological processes of heart and blood vessels. In addition, a number of drugs that regulate ERS was introduced, which may be used to treat cardiovascular diseases. This review may open new avenues for studying the pathogenesis of cardiovascular diseases and discovering novel drugs targeting ERS.

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Bone marrow deficiency of TRPC3 channel reduces early lesion burden and necrotic core of advanced plaques in a mouse model of atherosclerosis

Cited by 44 publications

References 27 publications

Increased size and cellularity of advanced atherosclerotic lesions in mice with endothelial overexpression of the human TRPC3 channel

Increased size and cellularity of advanced atherosclerotic lesions in mice with endothelial overexpression of the human TRPC3 channel

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases

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