Abdominal aortic aneurysm (AAA) is characterized by the thinning of the media and a permanent dilation of the aorta. The medial layer is a major location of degradative remodeling responsible for aneurysm formation. Inflammatory vascular smooth muscle cells (VSMCs) contribute to vascular inflammation during AAA progression, and medial VSMC senescence has been suggested to be detrimental in AAA. Myocardin related transcription factor A (MRTFA) is a member of MRTF family which has been shown to positively linked to coronary artery diseases and contribute to pathological vascular remodeling. Our preliminary data showed that MRTFA was markedly increased in aneurysmal vessels, and loss of MRTFA completely protected mice from AAA formation and rupture in an angiotensin II (Ang II)-induced AAA model, which indicated that MRTFA was an essential gene candidate for AAA pathogenesis. Mechanistically, depletion of MRTFA in cultured VSMCs decreased the expression of several key proinflammatory mediators in AAA including IL6 and MMP2. The activation of VSMC inflammation by MRTFA was likely achieved via a novel interaction between MRTFA and KILN, a new proinflammatory long noncoding RNA (lncRNA) we have discovered. Further, depletion of MRTFA alleviated Ang II-induced VSMC senescence, as evidenced by the reduced expression of senescence markers, CDKN1A and CDKN2A, as well as NOX4, a central regulator of oxidative stress contributing to cellular senescence. Therefore, we hypothesize that MRTFA promotes AAA formation through its activation of VSMC inflammation and senescence involving its physical interaction with KILN and upregulation of NOX4, respectively. Our goal is to define a novel regulator for both VSMC inflammation and senescence leading to AAA formation, which will provide novel insights into the therapeutic strategy for aortic aneurysm, a devastating human disease without effective therapy. We propose 2 specific aims to test our hypothesis and achieve this goal. Aim 1 will determine the role of MRTFA in Ang II-induced AAA formation and relevant pathological changes. We will use MRTFA-/-; ApoE-/- knockout mice and a pharmacological MRTFA inhibitor. Aim 2 will elucidate the underlying mechanisms by which MRTFA promotes Ang II-induced AAA formation. We will investigate whether MRTFA activates VSMC proinflammation through cooperative binding with the proinflammatory lncRNA, KILN, and promotes VSMC senescence via transactivating NOX4 gene expression.
|Program type||Predoctoral Fellowship|
|Effective start/end date||01/01/2019 → 12/31/2020|