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.
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.
From the Departments of Internal Medicine and.
Callie S
CS
Kwartler
From the Departments of Internal Medicine and.
Jiyuan
J
Chen
Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, Texas 77030.
Dhananjay
D
Thakur
the Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555.
Shumin
S
Li
From the Departments of Internal Medicine and.
Kedryn
K
Baskin
From the Departments of Internal Medicine and.
Shanzhi
S
Wang
the Departments of Internal Medicine (Cardiology) and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, and.
Zhao V
ZV
Wang
the Department of Medicine, University of Colorado, Denver, Colorado 80217.
Lori
L
Walker
the Departments of Internal Medicine (Cardiology) and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, and.
Joseph A
JA
Hill
the Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555.
Henry F
HF
Epstein
From the Departments of Internal Medicine and.
Heinrich
H
Taegtmeyer
From the Departments of Internal Medicine and Dianna.M.Milewicz@uth.tmc.edu.
Dianna M
DM
Milewicz
D000818:Animals; D001343:Autophagy; D020013:Calcium Signaling; D058674:Chromosome Duplication; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D059865:Endoplasmic Reticulum Stress; D015870:Gene Expression; D006801:Humans; D051379:Mice; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism* / Q000502:physiology; D018995:Myosin Heavy Chains / Q000235:genetics* / Q000378:metabolism*; D056811:Unfolded Protein Response
C509903:MYH11 protein, human; D018995:Myosin Heavy Chains
Autophagy; ER Stress; Myosin; Protein Turnover; Thoracic Aortic Aneurysms and Dissections; Unfolded Protein Response; Vascular Smooth Muscle Cells