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- W119346919 abstract "Following myocardial infarction (MI), cardiac fibroblasts (CF) proliferate, undergo myofibroblast transformation and generate excess extracellular matrix (ECM). Increased ECM production leads to fibrosis resulting in diastolic dysfunction, ultimately reducing cardiac output. Sphingosine-1-phosphate (S1P), a bioactive lysophospholipid, regulates function of numerous cell types, including certain cardiac cells. The research presented in this dissertation determined the role of S1P in promoting pro-fibrotic actions of CF. Real-time PCR of adult mouse ventricular CF and cardiac myocytes (CM) revealed that, by comparison to CM, CF exhibit higher expression of S1P receptors and sphingosine kinase-1 (SphK1), the enzyme responsible for S1P production. In agreement with this data, both cardiac tissue and isolated cells reveal large cellular pools of S1P in CF, while low levels of S1P are detected in CM. S1P enhanced CF proliferation in an ERK-dependent manner. S1P increased expression of [alpha]-smooth muscle actin ([alpha]-SMA; a myofibroblast marker) and induced collagen production. Both were Rho kinase and S1P₂ receptor-dependent. siRNA to S1P₁ and S1P₃ enhanced basal [alpha]-SMA and collagen production suggesting (1) that myofibroblast transformation and collagen production are inhibited by signaling through these receptors and (2) S1P stimulates basal collagen production through autocrine and paracrine signaling. The well-known pro-fibrotic mediator, TGF- [beta], upregulated SphK1 expression and activity and this was necessary for TGF-[beta]-stimulated collagen production by CF. The anti-S1P monoclonal antibody (mAb) inhibited TGF-[beta]-stimulated collagen production further suggesting that CF utilize autocrine and paracrine signaling wherein SphK produced S1P intracellularly which was secreted and activated S1P₂ located on the cell surface. The anti-S1P mAb, when administered 48 hr after a permanent coronary artery ligation, abolished perivascular fibrosis at two weeks as compared to saline-treated control animals. These findings demonstrate that the S1P signaling machinery is increased in CF compared to CM and that CF may serve as a source of S1P in the heart. In addition, S1P promotes pro-fibrotic function of isolated CF both on its own and in conjunction with TGF-[beta]. Lastly, the anti-S1P antibody reduces cardiac fibrosis in mice following MI. Thus, the anti-S1P mAb may serve as a novel therapeutic to attenuate CF function and resultant tissue fibrosis following ischemic cardiac injury" @default.
- W119346919 created "2016-06-24" @default.
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- W119346919 date "2008-01-01" @default.
- W119346919 modified "2023-09-27" @default.
- W119346919 title "The role of sphingosine -1 -phosphate in cardiac remodeling" @default.
- W119346919 hasPublicationYear "2008" @default.
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