Atherosclerosis is a progressive disease that is a leading cause of death in the Western world. Remarkably, despite decades of research, there remain major ambiguities regarding the role of smooth muscle cells (SMC) in lesion pathogenesis, as well as mechanisms that control plaque stability and the probability of plaque rupture with possible myocardial infarction (MI) or stroke. The general dogma is that SMC are primarily involved in late not early stage lesions, and that their primary role is atheroprotective by contributing to formation of a fibrous cap. However, recent Nature Medicine studies by our lab involving simultaneous SMC-specific lineage tracing and knockout (KO) of the stem cell pluripotency genes, Oct4 or Klf4 provided compelling evidence that SMC play a much greater role in lesion pathogenesis than has been generally appreciated. Key findings included our showing that: 1) >80% of SMC-derived cells within advanced lesions of ApoE-/- mice lack detectable expression of typical SMC markers; 2) 30-40% of SMC- derived cells within both advanced mouse and human lesions lack detectable SMC markers and have activated markers of M?s; and 3) SMC can have major beneficial or detrimental effects on lesion pathogenesis depending on the nature of their phenotypic transitions. Studies in this proposal will test the hypothesis that SMC phenotypic transitions can exert dominant atheroprotective or atheropromoting effects on late stage lesion pathogenesis and represent a novel therapeutic target for treating advanced atherosclerosis.
Aim 1 will test the hypothesis that Klf4-dependent transitions in SMC phenotype and function exacerbate lesion pathogenesis in early and late stages of atherosclerosis, and will include defining distinct atheroprotective SMC phenotypes induced by SMC-specific conditional KO of Klf4 based on complementary flow cytometric and high resolution confocal analyses of unique marker panels derived from our in vivo RNAseq and Klf4/Oct4 ChIPseq genomic analyses of advanced brachiocephalic (BCA) lesions and cross referenced to genes linked to increased human CAD risk. We will also determine if delayed SMC specific conditional KO of Klf4 after establishment of advanced lesions also induces favorable changes in lesion pathogenesis.
Aim 2 will test the hypothesis that Oct4-dependent transitions in SMC phenotype and function promote plaque stabilization by enhancing investment of SMC into a protective fibrous cap and reducing their transition to a pro-inflammatory state. We will also test if SMC phenotypes identified in our mouse studies also occur in human lesions and define which phenotypes correlate with stable versus unstable lesions.
Aim 3 will determine if SMC phenotypic changes within advanced lesions are reversible, and if treatment SMC lineage tracing mice with advanced lesions with a PCSK9 inhibitor promotes beneficial changes in SMC phenotype and/or overall lesion pathogenesis. Studies may lead to identification of novel therapeutic approaches for reducing late stage clinical complications of atherosclerosis by inducing beneficial (plaque stabilizing) changes in SMC phenotype and function.
/Relevance: Atherosclerosis is a progressive disease that is a leading cause of death in the world. Remarkably, despite decades of research, very little is known about late stage lesion development and mechanisms that result in the rupture of advanced atherosclerotic lesions leading to catastrophic thrombotic events including a heart attack (i.e. myocardial infarction) or a stroke. Drugs for reducing the probability of plaque rupture have largely focused on lipid lowering compounds and anti-inflammatory agents which thus far have only modestly reduced event rates or had no effect. The long term goal of studies in this proposal is to develop novel approaches for reducing the late stage clinical complications of atherosclerosis by inducing vascular smooth muscle cells (SMC) to undergo favorable changes in phenotype-function that promote formation of a thick mechanically stable fibrous cap (i.e. analogous to a patch on a tire) on advanced atherosclerotic lesions, thereby reducing the probability of them rupturing and setting off a possible heart attack or stroke.
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