Abstract 9860: P38MAPK Deficiency in VSMCs Mitigates Abdominal Aortic Aneurysm and Atherosclerosis Progression via Promoting MKL1 Ubiquitin Proteasome Degradation

Abstract

Cardiovascular diseases (CVD) are the leading cause of death in developed countries. Two major manifestations of CVD are aortic aneurysm and atherosclerosis, which are devastating and lack effective pharmacological therapy. The stress responsive pathway, p38 mitogen-activated protein kinase (MAPK), has been reported as a pivotal regulator in diverse processes, including cell proliferation, migration, inflammation, and apoptosis, contributing to cardiovascular development and pathology. However, a detailed understanding of the mechanistic role of p38MAPK in vascular smooth muscle cells (VSMCs) in the pathogenesis of aortic aneurysm and atherosclerosis has yet to be elucidated. Using a VSMC-specific lineage tracing reporter system, we showed that the phosphorylated form of p38MAPK (p-p38MAPK) was markedly elevated in VSMCs of aneurysmal vessels. VSMC-specific p38α ( Mapk14 ) knockout mice displayed attenuated abdominal aortic aneurysm (AAA) and atherosclerotic lesion formation compared to wild-type control mice. Further, loss of MAPK14 in VSMCs abolished the protein expression of multiple ER stress markers, including BIP, Protein Disulfide Isomerase (PDI), and ATF4, which was accompanied by the downregulation of the cleaved Caspase-3 and upregulation of BCL2 protein. This indicates a crucial role of p38MAPK in potentiating ER stress and apoptosis. Interestingly, aortas from VSMC-MAPK14 null mice displayed dramatically reduced protein levels of MKL1, a vital transcription factor with a well-recognized role in promoting AAA and atherosclerosis progression via regulating vascular apoptosis. In vitro, deficiency of p38MAPK in VSMCs via siRNA or SB203580, a selective inhibitor of p38MAPK pathway, downregulated whereas forced expression of MKK6 (activates p38MAPK) increased MKL1 protein expression. Finally, activation of p38MAPK inhibited MKL1 ubiquitination, which was partially rescued by SB203580. Collectively, our data demonstrated a critical role of VSMC-p38MAPK in promoting AAA and atherosclerosis progression, likely through stabilization of MKL1 via p38MAPK-dependent inhibition of MKL1 ubiquitin proteasome degradation.