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

Kwartler, Callie S.; Chen, Jiyuan; Thakur, Dhananjay; Li, Shumin; Baskin, Kedryn K.; Wang, Shanzhi; Wang, Zhao V.; Walker, Lori A.; Hill, Joseph A.; Epstein, Henry F.; Taegtmeyer, Heinrich; Milewicz, Dianna M.

doi:10.1074/jbc.m113.499277

Cited by 34 publications

(26 citation statements)

References 62 publications

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“…Activation of autophagy occurred coincident with the loss of myocardin, raising the intriguing hypothesis that modulation of the vascular SMC phenotype (and repression of SMC contractile genes) may be accelerated by ER stress-induced autophagy of SMC contractile elements required to preserve cellular energy stores and metabolism. Consistent with a model wherein turnover of SMC contractile proteins triggers ER stressinduced autophagy, overexpression of SMMHC led to the activation of UPR and autophagic turnover in vascular SMCs (14). However, late-stage SMC apoptosis was observed, suggesting that induction of autophagy is ultimately not sufficient to preserve vascular (and visceral) SMCs required for cardiovascular homeostasis and function of visceral tissues.…”

Section: Discussionsupporting

confidence: 66%

Myocardin is required for maintenance of vascular and visceral smooth muscle homeostasis during postnatal development

Huang

Wang

Wright³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Myocardin is a muscle-restricted transcriptional coactivator that activates a serum response factor (SRF)-dependent gene program required for cardiogenesis and embryonic survival. To identify myocardin-dependent functions in smooth muscle cells (SMCs) during postnatal development, mice harboring a SMC-restricted conditional, inducible Myocd null mutation were generated and characterized. Tamoxifen-treated SMMHC-Cre ERT2 /Myocd F/F conditional mutant mice die within 6 mo of Myocd gene deletion, exhibiting profound derangements in the structure of great arteries as well as the gastrointestinal and genitourinary tracts. Conditional mutant mice develop arterial aneurysms, dissection, and rupture, recapitulating pathology observed in heritable forms of thoracic aortic aneurysm and dissection (TAAD). SMCs populating arteries of Myocd conditional mutant mice modulate their phenotype by down-regulation of SMC contractile genes and up-regulation of extracellular matrix proteins. Surprisingly, this is accompanied by SMC autonomous activation of endoplasmic reticulum (ER) stress and autophagy, which over time progress to programmed cell death. Consistent with these observations, Myocd conditional mutant mice develop remarkable dilation of the stomach, small intestine, bladder, and ureters attributable to the loss of visceral SMCs disrupting the muscularis mucosa. Taken together, these data demonstrate that during postnatal development, myocardin plays a unique, and important, role required for maintenance and homeostasis of the vasculature, gastrointestinal, and genitourinary tracts. The loss of myocardin in SMCs triggers ER stress and autophagy, which transitions to apoptosis, revealing evolutionary conservation of myocardin function in SMCs and cardiomyocytes. Mice harboring a null mutation in the myocardin gene (Myocd) exhibit a block in cardiomyocyte proliferation accompanied by a dramatic increase in cardiomyocyte apoptosis, leading to lethality at midgestation (5). Ablation of Myocd in the adult heart leads to heart failure and lethality attributable to a disruption in sarcomere structure accompanied by programmed cell death (6). By contrast, mice harboring a neural crest-restricted ablation of Myocd die in the perinatal period from patent ductus arteriosus (PDA) attributable to a block in the SMC contractile gene program (7).After more than a decade of study, fundamental questions regarding the function of myocardin in vascular SMCs during postnatal development as well as visceral SMCs populating the gastrointestinal and genitourinary tracts remain unanswered. Is myocardin required for SMC contractile gene expression and maintenance of arterial tone? What role, if any, does myocardin play in regulating expression of SRF-regulated SMC contractile genes in visceral SMCs? Do the related transcriptional coactivators MKL-1 and/or MKL-2 mediate redundant functions with myocardin in the adult vasculature or visceral tissues (4)? Is myocardin required for survival of vascular SMCs in a manner analogous to that it plays in c...

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Section: Discussionsupporting

confidence: 66%

Myocardin is required for maintenance of vascular and visceral smooth muscle homeostasis during postnatal development

Huang

Wang

Wright³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…These data indicate that haploinsufficiency for MYH11 does not appear to cause disease, whereas increased expression of MYH11 , as would occur with duplications leading to three copies of the gene, does predispose to acute aortic dissections. Studies exploring how increased expression of MYH11 leads to thoracic aortic disease identified increased autophagy and degradation of SM-MHC and endoplasmic reticulum stress in SMCs with overexpression of the myosin heavy chain 55 .…”

Section: Myh11 Mutationsmentioning

confidence: 99%

Altered Smooth Muscle Cell Force Generation as a Driver of Thoracic Aortic Aneurysms and Dissections

Milewicz

Trybus

Guo

et al. 2017

ATVB

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183

168

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The importance of maintaining contractile function in aortic smooth muscle cells (SMCs) is evident by the fact that heterozygous mutations in the major structural proteins or kinases controlling contraction lead to the formation of aneurysms of the ascending thoracic aorta that predispose to life-threatening aortic dissections. Force generation by SMC requires ATP-dependent cyclic interactions between filaments composed of SMC specific isoforms of α-actin (encoded by ACTA2) and myosin heavy chain (MYH11). ACTA2 and MYH11 mutations shown to disrupt this cyclic interaction predispose to thoracic aortic disease. Movement of the myosin motor domain is controlled by phosphorylation of the regulatory light chain (RLC) on the myosin filament, and loss-of-function mutations in the dedicated kinase for this phosphorylation, myosin light chain kinase (MYLK) also predispose to thoracic aortic disease. Finally, a mutation in the cGMP-activated protein kinase (PRKG1) results in constitutive activation of the kinase in the absence of cGMP, thus driving SMC relaxation in part through increased de-phosphorylation of the RLC, and predisposes to thoracic aortic disease. Furthermore, SMCs cannot generate force without connections to the extracellular matrix (ECM) through focal adhesions, and mutations in the major protein in the ECM, fibrillin-1, linking SMCs to the matrix also cause thoracic aortic disease in individuals with Marfan syndrome. Thus, disruption of the ability of the aortic SMC to generate force through the elastin-contractile units in response to pulsatile blood flow may be a primary driver for thoracic aortic aneurysms and dissections.

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“…AAD patients were included in the International Registry of Aortic Dissection (IRAD) that was set up in 1996 by cardiovascular specialists committed to expanding current knowledge of aortic dissection with the goal of improving patient outcomes, with data from 1 January 1996 to 2015. The structure and methods of IRAD have been published [23, 24] and patients gave the hospital their written informed consent.…”

Section: Methodsmentioning

confidence: 99%

A pilot observational study on magnesium and calcium imbalance in elderly patients with acute aortic dissection

et al. 2017

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BackgroundMagnesium (Mg) and calcium (Ca) are the principal essential elements involved in endothelial cell homeostasis. Extracellular changes in the levels of either alter endothelial contraction and dilatation. Consequently Mg and Ca imbalance is associated with a high risk of endothelial dysfunction, the main process observed during acute aortic dissection (AAD); in this clinical condition, which mainly affects elderly men, smooth muscle cell alterations lead to intimal tears, creating a false new lumen in the media of the aorta. AAD patients have a high risk of mortality as a result of late diagnosis because often it is not distinguished from other cardiovascular diseases.We investigated Mg and Ca total circulating levels and the associated pro-inflammatory mediators in elderly AAD patients, to gain further information on the pathophysiology of this disorder, with a view to suggesting newer and earlier potential biomarkers of AAD.ResultsTotal circulating Mg and Ca levels were both lower in AAD patients than controls (p < 0.0001). Using Ca as cut-off, 90% of AAD patients with low Ca (<8.4 mg/dL) came into the type A classification of AAD. Stratifying AAD according to this cut-off, Mg was lower in patients with lower total Ca.Compared to controls, both type A and B AAD patients had higher levels of all the pro-coagulant and pro-inflammatory mediators analyzed, including sP-sel, D-dimer, TNF-α, IL-6, and CRP (p < 0.05). Dividing types A and B using the Stanford classification, no significant differences were found (p > 0.05) The levels of both ICAM-1 and EN-1 were lower in AAD than in a control group (p < 0.0001 and p < 0.05 respectively).ConclusionsThese findings suggest that low Mg and Ca in AAD elderly patients may contribute to altering normal endothelial physiology and also concur in changing the normal concentrations of different mediators involved in vasodilatation and constriction, associated with AAD onset and severity.

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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

Cited by 34 publications

References 62 publications

Myocardin is required for maintenance of vascular and visceral smooth muscle homeostasis during postnatal development

Myocardin is required for maintenance of vascular and visceral smooth muscle homeostasis during postnatal development

Altered Smooth Muscle Cell Force Generation as a Driver of Thoracic Aortic Aneurysms and Dissections

A pilot observational study on magnesium and calcium imbalance in elderly patients with acute aortic dissection

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