Myosin Phosphatase Regulatory Pathways

Lincoln, Thomas M.

doi:10.1161/01.res.0000255894.25293.82

Cited by 48 publications

(25 citation statements)

References 25 publications

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“…This process enables the muscle to sustain a contraction once the initial calcium transient has dissipated. There are two mechanisms for calcium sensitization: a DAG-PLC-PKC pathway and a RhoA pathway (Lincoln 2007).…”

Section: Calcium Sensitizationmentioning

confidence: 99%

Signaling in Muscle Contraction

Kuo

Ehrlich

2015

Cold Spring Harb Perspect Biol

286

216

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SUMMARYSignaling pathways regulate contraction of striated (skeletal and cardiac) and smooth muscle. Although these are similar, there are striking differences in the pathways that can be attributed to the distinct functional roles of the different muscle types. Muscles contract in response to depolarization, activation of G-protein-coupled receptors and other stimuli. The actomyosin fibers responsible for contraction require an increase in the cytosolic levels of calcium, which signaling pathways induce by promoting influx from extracellular sources or release from intracellular stores. Rises in cytosolic calcium stimulate numerous downstream calcium-dependent signaling pathways, which can also regulate contraction. Alterations to the signaling pathways that initiate and sustain contraction and relaxation occur as a consequence of exercise and pathophysiological conditions.

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Section: Calcium Sensitizationmentioning

confidence: 99%

Signaling in Muscle Contraction

Kuo

Ehrlich

2015

Cold Spring Harb Perspect Biol

286

216

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“…Secondary osteoarthritis (OA) associated with intraarticular injury is a common clinical presentation [1]. Following anterior cruciate ligament (ACL) rupture, hypertrophy of the medial collateral ligament (MCL), capsule and synovium occur [2], preceding meniscal tears, cartilage lesions, and sub-chondral sclerosis ultimately leading to osteoarthritis [2].…”

mentioning

confidence: 99%

“…1 A volume based ratiometric analysis of the endothelial volume (CD31 label) to a-SMA content has been previously utilized to determine the composition of angiogenic vessels, 2,3 and using similar methods will define the vascular anatomy of the MCL in ACL-t knee.…”

mentioning

confidence: 99%

Vascular structure and function in the medial collateral ligament of anterior cruciate ligament transected rabbit knees

et al. 2014

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To determine if decreased vascular responsiveness in the medial collateral ligament (MCL) of anterior cruciate ligament transected (ACL-t) rabbit knees is due to pericyte deficiency associated with angiogenesis. Vascular responses to potassium chloride (KCl), phenylephrine, acetylcholine, and sodium nitroprusside (SNP) were evaluated in ACL-t rabbit knees (n ¼ 6) and control knees (n ¼ 5) using laser speckle perfusion imaging. Ligament degeneration was determined by ultrasound imaging. Vascular and pericyte volume were measured using quantitative immunohistochemical volumetric analysis using CD31 and a-smooth muscle actin antibodies with co-localization analysis. Perfusion was increased in the ACL-t rabbits 2.5-fold. Responsiveness to phenylephrine, SNP, and acetylcholine was significantly decreased in the ACL knee while no change in KCl responses was seen. MCL ultrasound imaging revealed decreased collagen organization, increased ligament thickness, and increased water content in the ACL-t MCL. Vascular Volume was increased fourfold in ACL deficient knees, while pericyte volume to endothelial volume was not changed. No difference in CD31 and a-SMA co-localization was found. Blood vessels in the MCL of ACL-t knees do not lack smooth muscle. [2]. Our focus has centered on the pathologic changes that occur in the MCL following rupture of the anterior cruciate ligament. Our hope is that understanding early secondary OA pathology future interventions may be developed to preserve joint function and improve outcomes.The rabbit ACL transected (ACL-t) model has been extensively tested and is well known model of secondary OA having a reliable and reproducible natural history [3]. Joint instability induces osteoarthritic degeneration of rabbit knees, whereas immediate ACL reconstruction prevents joint degeneration [7]. The MCL tensile strength decreases after ACL-t, exacerbating joint instability [7]. A strong angiogenic response occurs in the MCL following ACL-t [8].The MCL vasculature does not respond appropriately to vasoactive mediators such as phenylephrine (PHE) and acetylcholine (ACH) after ACL-t [9,10].These processes are known as endothelial dysfunctionloss of vasodilatory responses mediated through the endothelium; and vascular dysfunction-loss of vasocontractile responses mediated through smooth muscle. Typically endothelial and vascular dysfunction are associated with inflammation [11]. Alternatively, angiogenesis may lead to decreased vascular smooth muscle and therefore decreased dilatory and contractile responses as has been found in synovium of rheumatoid arthritis patients [12].Quantification of the a-smooth muscle actin (a-SMA) content can be utilized to determine the anatomic state of blood vessels and if these vessels are capable of vasoregulation. 1 A volume based ratiometric analysis of the endothelial volume (CD31 label) to a-SMA content has been previously utilized to determine the composition of angiogenic vessels, 2,3 and using similar methods will define the vascular anatomy of the MC...

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“…4,5 Phosphorylation at Thr696 inhibits the catalytic activity of MP whereas Thr850 phosphorylation reduces binding of MYPT1 to myosin. 44 A recent study showed that treatment with LY83583 induces MYPT1 phosphorylation at Thr850 in rat small pulmonary arteries. 45 In another study, treatment with H 2 O 2 for 1 h enhances MYPT1 phosphorylation at both Thr696 and Thr850 in porcine pulmonary artery.…”

Section: Discussionmentioning

confidence: 99%

ROS-mediated downregulation of MYPT1 in smooth muscle cells: a potential mechanism for the aberrant contractility in atherosclerosis

Cheng

Tsai

et al. 2013

Laboratory Investigation

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Reactive oxygen species (ROS) mediates the aberrant contractility in hypertension. Abnormal contractility occurs in atherosclerotic vessels but changes in proteins that regulate contractility remain poorly understood. Myosin phosphatase (MP) activity, which regulates smooth muscle relaxation, is regulated by the phosphorylation of its regulatory subunit, MP targeting subunit 1 (MYPT1). In the present study, we examined the roles of ROS in MP subunit expression both in cultured human aortic smooth muscle cells (HASMCs) and during atherosclerosis progression in apolipoprotein E-knockout (apoE-KO) mice. Furthermore, the effect of decreased MYPT1 on actin cytoskeleton and cell migration activity was assessed in HASMCs. Short hairpin RNA-mediated knockdown of MYPT1 increased stress fibers and attenuated platelet-derived growth factor-induced cell migration in HASMCs. Superoxide anion-inducing agent LY83583 downregulated MYPT1 mRNA and protein levels, but did not affect the phosphorylation of MYPT1 and catalytic subunit of MP, PP1d. The LY83583-induced decrease in MYPT1 was abolished by co-treating with superoxide dismutase or by inhibiting NADPH oxidase with diphenyleneiodonium. Treatment of peroxynitrite, but not hydrogen peroxide (H 2 O 2 ), downregulated MYPT1 protein expression and induced MYPT1 phosphorylation without affecting mRNA levels. Co-treatment with a proteasome inhibitor, MG-132, eliminated peroxynitrite-induced MYPT1 downregulation. In apoE-KO mice, MYPT1 protein, but not mRNA, levels were markedly decreased in 16-week-and 24-week-old mice. Oral estrogen treatment, which was previously shown to decrease aortic ROS levels, upregulated aortic MYPT1 expression. Moreover, reduction in MYPT1 expression correlated with increased aortic sensitivity toward vasoconstrictors. These results suggested that during atherosclerosis progression oxidative stress mediates the downregulation of MYPT1, which may inhibit smooth muscle cell migration and contribute to the aberrant contractility.Laboratory Investigation (2013) 93, 422-433; doi:10.1038/labinvest.2013 published online 18 February 2013 KEYWORDS: atherosclerosis; contractility; myosin phosphatase; reactive oxygen species; smooth muscle At the molecular level, phosphorylation of the 20-kDa myosin light chains (MLC 20 ) is a key determinant for smooth muscle contraction. MLC 20 phosphorylation levels are determined by the activity ratio between myosin light chain kinase (MLCK) and myosin phosphatase (MP). 1 Although MLCK activation depends on cytoplasmic calcium concentration, MP activity is subject to modulation by various signaling molecules. 2 MP is a heterotrimer comprised of a 37-to 38-kDa catalytic subunit (PP1d), a 110-to 130-kDa regulatory subunit (MP targeting subunit 1; MYPT1), and a 20-kDa subunit of unknown function. The phosphorylation of MYPT1 by protein kinases is a major regulatory mechanism for MP that results in either the inhibition or enhancement of MP activity. 3 Small GTPase RhoA and its effecter, Rho-kinase, inhibit MP activity through ...

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Myosin Phosphatase Regulatory Pathways

Cited by 48 publications

References 25 publications

Signaling in Muscle Contraction

Signaling in Muscle Contraction

Vascular structure and function in the medial collateral ligament of anterior cruciate ligament transected rabbit knees

ROS-mediated downregulation of MYPT1 in smooth muscle cells: a potential mechanism for the aberrant contractility in atherosclerosis

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