Cardiac functional improvement in rats with myocardial infarction by up-regulating cardiac myosin light chain kinase with neuregulin

Gu, Xiang; Liu, Xifu; Xu, Dazhi; Li, Xinyan; Yan, M.; Qi, Ying; Yan, Weihai; Wang, Wenqing; Pan, Jing; Xu, Yecheng; Xi, Bing; Cheng, Leilei; Jia, Jianguo; Wang, Keqiang; Ge, Junbo; Zhou, Meijuan

doi:10.1093/cvr/cvq223

Cited by 56 publications

(45 citation statements)

References 34 publications

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“…62, 63 In animal models of myocardial infarction, the expression level of cMLCK in the heart has been found to be reduced. 18, 52 In addition, pressure overload also led to a marked reduction in cMLCK and phosphorylated MLC2v in the heart 1 week after thoracic aortic constriction surgery. 25 Interestingly, the reduction in the cMLCK protein level in pressure-overloaded hearts was mediated by upregulation of the ubiquitin-proteasome degradation system.…”

Section: Pks and Protein Phosphatase Regulation Of Mlc2 Phosphorylatimentioning

confidence: 99%

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Biochemical and Physiological Regulation of Cardiac Myocyte Contraction by Cardiac-Specific Myosin Light Chain Kinase

Tsukamoto

Kitakaze

2013

Circ J

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Section: Pks and Protein Phosphatase Regulation Of Mlc2 Phosphorylatimentioning

confidence: 99%

“…Neuregulin, which activates ErbB receptor tyrosine kinase, has been reported to enhance the expression of cMLCK with a concomitant increase in MLC2v phosphorylation and improved cardiac performance after myocardial infarction in rats. 52 …”

Section: Physiological Regulators Of Cmlck Expression and Activitymentioning

confidence: 99%

Biochemical and Physiological Regulation of Cardiac Myocyte Contraction by Cardiac-Specific Myosin Light Chain Kinase

Tsukamoto

Kitakaze

2013

Circ J

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“…Considering that cMLCK was identified in human heart failure (14), it may play a role not only in the physiological performance of the heart but also in adaptive responses to pathophysiological stresses. Infu-sion of neuregulin, a peptide that activates ErbB receptor tyrosine kinases in cardiac myocytes, increases expression of cMLCK, with increased RLC phosphorylation associated with improved cardiac performance after myocardial infarction in rats (94). Administration of neuregulin to patients with stable chronic heart failure improves hemodynamic responses acutely and chronically (95).…”

Section: Rlc Phosphorylation May Be Involved In Heart Diseasesmentioning

confidence: 99%

Signaling to Myosin Regulatory Light Chain in Sarcomeres

Kamm

Stull

2011

Journal of Biological Chemistry

104

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“…Additional investigations are needed to establish specific cellular mechanisms involved, but recent results provide new perspectives. Infusion of neuregulin, a peptide that activates ErbB receptor tyrosine kinases in cardiac myocytes, increases expression of cMLCK with increased MLC2v phosphorylation associated with improved cardiac performance after myocardial infarction in rats (62). Administration of neuregulin to patients with stable chronic heart failure improves hemodynamic responses acutely and chronically (63).…”

Section: Measurements Cmlckmentioning

confidence: 99%

Cardiac Myosin Light Chain Kinase Is Necessary for Myosin Regulatory Light Chain Phosphorylation and Cardiac Performance in Vivo

Ding

Huang

Battiprolu

et al. 2010

Journal of Biological Chemistry

107

116

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In contrast to studies on skeletal and smooth muscles, the identity of kinases in the heart that are important physiologically for direct phosphorylation of myosin regulatory light chain (RLC) is not known. A Ca 2؉ /calmodulin-activated myosin light chain kinase is expressed only in cardiac muscle (cMLCK), similar to the tissue-specific expression of skeletal muscle MLCK and in contrast to the ubiquitous expression of smooth muscle MLCK. We have ablated cMLCK expression in male mice to provide insights into its role in RLC phosphorylation in normally contracting myocardium. The extent of RLC phosphorylation was dependent on the extent of cMLCK expression in both ventricular and atrial muscles. Attenuation of RLC phosphorylation led to ventricular myocyte hypertrophy with histological evidence of necrosis and fibrosis. Echocardiography showed increases in left ventricular mass as well as end-diastolic and end-systolic dimensions. Cardiac performance measured as fractional shortening decreased proportionally with decreased cMLCK expression culminating in heart failure in the setting of no RLC phosphorylation. Hearts from female mice showed similar responses with loss of cMLCK associated with diminished RLC phosphorylation and cardiac hypertrophy. Isoproterenol infusion elicited hypertrophic cardiac responses in wild type mice. In mice lacking cMLCK, the hypertrophic hearts showed no additional increases in size with the isoproterenol treatment, suggesting a lack of RLC phosphorylation blunted the stress response. Thus, cMLCK appears to be the predominant protein kinase that maintains basal RLC phosphorylation that is required for normal physiological cardiac performance in vivo.Sarcomeric proteins in myocytes account for contraction of the heart that depends on the molecular motor myosin in the thick filaments binding to actin in thin filaments to initiate shortening and force development (1-3). Myosin cross-bridges contain an actin-binding surface and ATP pocket in the motor domain that taper to an ␣-helical neck connecting to the myosin rod region responsible for the self-assembly into thick filaments. Two small protein subunits, the essential light chain and the phosphorylatable RLC, 2 wrap around each ␣-helical neck region providing mechanical stability (4). RLC is necessary for assembly of thick filaments in cardiac myocytes, and mutations in RLC are linked to inherited hypertrophic cardiomyopathy (5, 6). There are two types of cardiac RLCs, a ventricular myosin light chain, MLC2v, and an atrium-specific form, MLC2a (7).In heart and skeletal muscle Ca 2ϩ binds to troponin in the actin thin filament, thereby allowing myosin heads to attach to actin for sarcomeric force development and shortening (8). Additionally, phosphorylation of RLC in fast-twitch skeletal muscle fibers by a skeletal muscle-specific Ca 2ϩ /calmodulindependent MLCK modulates the contractile response by potentiating frequency-dependent force development (9 -11). In the heart, phosphorylation of multiple sarcomeric proteins adjusts myofilamen...

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Cardiac functional improvement in rats with myocardial infarction by up-regulating cardiac myosin light chain kinase with neuregulin

Abstract: Our results suggest that cMLCK is a downstream effector of rhNRG-1 involved in rhNRG-1-induced cardiac function improvement, and that myocardial cMLCK up-regulation can improve cardiac function in rats with MI.

Cited by 56 publications

References 34 publications

Biochemical and Physiological Regulation of Cardiac Myocyte Contraction by Cardiac-Specific Myosin Light Chain Kinase

Biochemical and Physiological Regulation of Cardiac Myocyte Contraction by Cardiac-Specific Myosin Light Chain Kinase

Signaling to Myosin Regulatory Light Chain in Sarcomeres

Cardiac Myosin Light Chain Kinase Is Necessary for Myosin Regulatory Light Chain Phosphorylation and Cardiac Performance in Vivo

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