Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY Abdominal aortic aneurysm (AAA) is a devastating disease carrying high morbidity and mortality due to the high likelihood of fatal dissection and rupture. There are currently no proven pharmaceutical treatments to prevent AAA progression. VSMC degeneration contributes largely to AAA pathogenesis, but the mechanism remains elusive. The ubiquitin proteasome system (UPS) serves as an essential protein quality control mechanism by degrading misfolded proteins and surplus normal proteins. While proteotoxicity resulting from insufficient UPS function has been widely accepted as an important mechanism for multiple degenerative human conditions, the implication of UPS dysfunction in AAA is completely unknown. Our pathway analysis in human AAA tissues revealed an association of UPS function with AAA. In a mouse model of AAA, accumulation of ubiquitinated proteins, a hallmark of impaired UPS performance, precedes VSMC degeneration and AAA formation and is exacerbated with disease progression. This suggests that inadequate UPS performance may act as a novel mechanism underlying AAA etiology. MYOCD is a master switch of VSMC contractile gene program. How MYOCD is regulated and functions in AAA is unknown. Bulk RNA-seq in VSMCs showed an enrichment of UPS- related pathways in the top MYOCD-upregulated gene programs besides those relevant to VSMC contraction. Forced expression of MYOCD improved UPS performance while suppressing VSMC degeneration in cultured VSMCs and VSMC-specific MYOCD transgenic (Tg) mice at the early stage of AAA formation. MYOCD increased the expression of NFE2L1 and KLHL3, two key players of UPS function. These lines of evidence suggest a novel role of MYOCD in UPS function. Phosphodiesterases (PDEs), by catalyzing the hydrolysis of cAMP and cGMP to specifically modulate cyclic nucleotide signaling, play critical roles in VSMC pathophysiology and are proven drug targets for multiple human diseases. We found that PDE10A was the most induced PDE family member during AAA formation, while MYOCD protein expression was suppressed. Inhibition of PDE10A increased MYOCD protein, improved UPS performance, and suppressed AAA formation. These exciting preliminary findings support a novel hypothesis that downregulation of MYOCD protein by PDE10A impairs UPS performance, leading to VSMC degeneration and AAA. We propose three Aims to test this hypothesis. Aim 1 will use novel VSMC-specific Myocd knockout and Tg mice to determine the function of MYOCD in AngII-induced AAA model. Aim 2 will use a novel UPS reporter mouse line and biochemical assays to determine the importance of UPS function in MYOCD-regulated AAA and how MYOCD modulates UPS function. Aim 3 will determine how PDE10 promotes MYOCD protein degradation and PDE10A functions in UPS performance and AAA formation. This proposal will address for the first time the importance of UPS performance in VSMC degeneration and AAA formation, and elucidate a novel regulatory cascade comprising a druggable upstream modulator (PDE10A) and a downstream effector (MYOCD) in safeguarding UPS performance and proteostasis.
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