The SMAD3 signaling network in coronary artery disease risk

Stanford University, Stanford CA

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Abstract

Genome wide association studies (GWAS) have identified the transforming growth factor-b (TGFB) pathway as a prominent causal mechanism of coronary artery disease (CAD) risk. Through support provided by this funding mechanism, we have shown that disease protective TGFB canonical signaling factors SMAD3 and ZEB2 promote formation of disease-related transition smooth muscle cells (SMC) to a fibroblast-like phenotype, producing cells we term “fibromyocytes” (FMC) and inhibit SMC transition to a “chondromyocyte” (CMC) phenotype that is advanced by disease promoting genes such as PDGFD and TWIST1. In this renewal application we propose to extend these studies by investigating upstream signaling mediated by two TGFB superfamily members that link the BMP and TGFB pathways in a causal CAD regulatory network. Specifically, in this application we will pursue investigation of functional cellular interactions that are mediated by CAD associated factors BMP1 and TGFB1, which are linked in a feed-forward autoregulatory loop that impacts extracellular matrix (ECM) components and growth factors to mediate CAD risk through previously unexplored disease mechanisms. BMP1 is the primary regulator of TGFB1 bioavailability through post-translational prodomain processing, and as a metalloproteinase also directly activates other TGFB growth factors and extracellular matrix molecules such as collagens and lysyl oxidases that can promote stability of the fibrous cap. In keeping with previous studies, causal gene TGFB1 is expected to mediate SMC disease transition phenotypes through canonical signaling, but is also expected to mediate SMC cell state changes through unexplored non-canonical signaling pathways. We hypothesize that protein products of these two prominent CAD genes, BMP1 and TGFB1, regulate each other’s expression and function to modulate SMC phenotype transitions, ECM composition, and thus lesion integrity in the context of a CAD gene causal nexus. Thus, to better understand how BMP1 and TGFB1 interact to modulate the function of other growth and matrix factors that determine structure and stability of the plaque and fibrous cap, we propose the following Aims. Aim 1 studies will investigate the cellular anatomy of vascular lesions, as well as genome wide transcriptomic effects of SMC-specific Bmp1 modulation, in a mouse atherosclerosis model. In Aim 2, we will perform identical studies investigating genetic manipulation of Tgfb1 and compare transcriptional and lesion features of these two linked CAD causal factors. In Aim 3, we will use in vitro SMC models to further investigate how BMP1 regulates TGFB1 bioavailability and function of other ECM molecules involved in SMC- specific disease processes. These studies will significantly expand our understanding of genetic CAD mechanisms and identify targetable genes and pathways for new approaches to the treatment of CAD.