There is clear evidence that phenotypic switching of smooth muscle cells (SMC) plays a critical role in development of atherosclerotic disease, and end stage clinical consequences such as plaque rupture/thrombosis. However, the mechanisms and factors that regulate this process are poorly understood. In addition, although vascular inflammation plays a critical role in atherogenesis and its clinical sequelae, virtually nothing is known regarding the potential relationship between factors that regulate vascular inflammation and SMC phenotypic switching. The focus of this proposal is to test the hypothesis that the inflammatory cytokine IL-1b plays a critical role in regulating SMC phenotypic switching in response to vascular injury and experimental atherogenesis, and that the effects of IL-1b are mediated at least in part through a unique G/C repressor/TCE binding protein KLF4 we identified during the current funding period. In support of this hypothesis, we found that IL-1b, but not other cytokines, profoundly suppressed expression of all SMC marker genes tested including SM a-actin and SM MHC in cultured SMC while simultaneously markedly increasing expression of KLF4, as well as a number of genes implicated in control of plaque formation, remodeling, and stability such as MMP9 and collagen 8a1.
Aim 1 will determine mechanisms by which IL-1b suppresses expression of SMC differentiation marker genes and will include investigation of the role of KLF4, NFkB, Sp1, and inhibition of CArG-SRF-myocardin dependent transcription.
Aim 2 will test the hypothesis that KLF4, NFkB, and/or Sp1, in addition to suppressing expression of SMC marker genes (Aim 1) also play a role in modulating the effects of IL-1b on expression of MMP9, TIMPs, and ECM genes such as collagen 8a1 that play a critical functional role in lesion development, and/or plaque stability.
Aim 3 will determine the role and mechanisms by which IL-1b and IL-1 receptor signaling regulate SMC phenotypic switching in vivo in response to vascular injury or experimental atherosclerosis using a combination of our unique SMC promoter-reporter transgenic mice, as well as IL-1 receptor type 1, IL-1b, and ApoE knockout mice. Taken together, studies will provide novel insights regarding mechanisms that control phenotypic switching of SMC, and may contribute to development of novel therapies that selectively modulate this process to inhibit lesion formation and/or promote plaque stabilization.
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