Overexpression of Smooth Muscle Myosin Heavy Chain Leads to Activation of the Unfolded Protein Response and Autophagic Turnover of Thick Filament-associated Proteins in Vascular Smooth Muscle Cells

• Published in: The Journal of biological chemistry Vol. 289; no. 20; pp. 14075 - 14088
• Main Authors: Kwartler, Callie S., Chen, Jiyuan, Thakur, Dhananjay, Li, Shumin, Baskin, Kedryn, Wang, Shanzhi, Wang, Zhao V., Walker, Lori, Hill, Joseph A., Epstein, Henry F., Taegtmeyer, Heinrich, Milewicz, Dianna M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.05.2014; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Autophagy; Calcium Signaling; Cell Biology; Chromosome Duplication; Chromosomes, Human, Pair 16 - genetics; Endoplasmic Reticulum Stress; ER Stress; Gene Expression; Humans; Mice; Muscle Contraction; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - physiology; Myosin; Myosin Heavy Chains - genetics; Myosin Heavy Chains - metabolism; Protein Turnover; Thoracic Aortic Aneurysms and Dissections; Unfolded Protein Response; Vascular Smooth Muscle Cells; Vascular Smooth Muscle Cells; ER Stress; Protein Turnover; Myosin; Unfolded Protein Response; Autophagy; Thoracic Aortic Aneurysms and Dissections
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.499277

Duplications spanning nine genes at the genomic locus 16p13.1 predispose individuals to acute aortic dissections. The most likely candidate gene in this region leading to the predisposition for dissection is MYH11, which encodes smooth muscle myosin heavy chain (SM-MHC). The effects of increased expression of MYH11 on smooth muscle cell (SMC) phenotypes were explored using mouse aortic SMCs with transgenic overexpression of one isoform of SM-MHC. We found that these cells show increased expression of Myh11 and myosin filament-associated contractile genes at the message level when compared with control SMCs, but not at the protein level due to increased protein degradation. Increased expression of Myh11 resulted in endoplasmic reticulum (ER) stress in SMCs, which led to a paradoxical decrease of protein levels through increased autophagic degradation. An additional consequence of ER stress in SMCs was increased intracellular calcium ion concentration, resulting in increased contractile signaling and contraction. The increased signals for contraction further promote transcription of contractile genes, leading to a feedback loop of metabolic abnormalities in these SMCs. We suggest that overexpression of MYH11 can lead to increased ER stress and autophagy, findings that may be globally implicated in disease processes associated with genomic duplications. Genomic duplications involving the smooth muscle myosin heavy chain gene, MYH11, are associated with increased risk for acute aortic dissections. MYH11 overexpression causes increased turnover of contractile proteins through increased autophagy MYH11 duplications may predispose to aortic disease through increased turnover of contractile proteins and disruption of contractile signaling. Increased protein turnover may be an important mechanism by which genomic duplications cause human disease.