Acute heart failure with cardiomyocyte atrophy induced in adult mice by ablation of cardiac myosin light chain kinase

Massengill, Michael; Ashraf, Hassan; Chowdhury, Rajib; Chrzanowski, Stephen M.; Kar, Jeena; Warren, Sanford E.; Walter, Glenn A.; Zeng, Huadong; Kang, Byung-Ho; Anderson, Robert H.; Moss, Richard L.; Kasahara, Hideko

doi:10.1093/cvr/cvw069

Cited by 32 publications

(58 citation statements)

References 47 publications

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“…CaM, a known transducer of Ca 2+ signal, activates CaMKII45 to directly phosphorylate cMyBP‐C, which is a thick filament protein with physiological significance for normal myocardial contractility and stability and serves as a convergent node for signalling processes in the cardiomyocyte 46, 47. Activation of cMLCK, also regulated by CaM, appears to be pivotal to maintain the phosphorylation of MLC2v, which functions as an essential component of thick myofilament assembly and plays a critical role in maintaining normal myocardial contractility and function 48, 49. The dephosphorylation of both MLC2v and cMyBP‐C is associated with a declined cardiac function in failing human hearts and animal models of HF 46, 48.…”

Section: Discussionmentioning

confidence: 99%

Lycium barbarum polysaccharides restore adverse structural remodelling and cardiac contractile dysfunction induced by overexpression of microRNA‐1

Zhang

Niu

et al. 2018

J Cellular Molecular Medi

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MicroRNA‐1 (miR‐1) stands out as the most prominent microRNA (miRNA) in regulating cardiac function and has been perceived as a new potential therapeutic target. Lycium barbarum polysaccharides (LBPs) are major active constituents of the traditional Chinese medicine based on L. barbarum. The purpose of this study was to exploit the cardioprotective effect and molecular mechanism of LBPs underlying heart failure. We found that LBPs significantly reduced the expression of myocardial miR‐1. LBPs improved the abnormal ECG and indexes of cardiac functions in P‐V loop detection in transgenic (Tg) mice with miR‐1 overexpression. LBPs recovered morphological changes in sarcomeric assembly, intercalated disc and gap junction. LBPs reversed the reductions of CaM and cMLCK, the proteins targeted by miR‐1. Similar trends were also obtained in their downstream effectors including the phosphorylation of MLC2v and both total level and phosphorylation of CaMKII and cMyBP‐C. Collectively, LBPs restored adverse structural remodelling and improved cardiac contractile dysfunction induced by overexpression of miR‐1. One of the plausible mechanisms was that LBPs down‐regulated miR‐1 expression and consequently reversed miR‐1‐induced repression of target proteins relevant to myocardial contractibility. LBPs could serve as a new, at least a very useful adjunctive, candidate for prevention and therapy of heart failure.

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Section: Discussionmentioning

confidence: 99%

Lycium barbarum polysaccharides restore adverse structural remodelling and cardiac contractile dysfunction induced by overexpression of microRNA‐1

Zhang

Niu

et al. 2018

J Cellular Molecular Medi

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“…Floxed-Mylk3 homozygous mice ( Mylk3 flox ∕ flox ) (Massengill et al, 2016) were bred with transgenic mice carrying the Cre-ER ™ gene under CMV promoter, Tg(CAGGS-Cre-ER ™ ) (Hayashi and McMahon, 2002). Subsequent matings between offspring generated Mylk3 flox ∕ flox / Tg-CAGGS-Cre-ER ™, Mylk3 wild ∕ wild /Tg-CAGGS-Cre-ER ™, and Mylk3 flox ∕ flox on a mixed genetic background, mainly C57BL/6J.…”

Section: Methodsmentioning

confidence: 99%

“…Mice were anesthetized with 1.5–2% isoflurane for M-mode ultrasound imaging of the left ventricles using Vevo700 as described previously (Briggs et al, 2008; Takeda et al, 2009; Warren et al, 2012; Massengill et al, 2016). …”

Section: Methodsmentioning

confidence: 99%

“…It is not yet known, to the best of our knowledge, whether phosphorylation of MLC2, or its responsive kinase, cardiac myosin light chain kinase (cMLCK), is reduced in children with heart failure. When, in genetically modified mice, cMLCK encoded by Mylk3 gene, was ablated either from the germline or inducibly in adulthood, both populations of cMLCK-deficient mice exhibited heart failure (Warren et al, 2012; Massengill et al, 2016). Knockout in the germline, however, leads to compensatory cardiac hypertrophy, while induction of the knockout in adult mice results in cardiomyocyte atrophy.…”

Section: Introductionmentioning

confidence: 99%

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Heart Failure Induced by Perinatal Ablation of Cardiac Myosin Light Chain Kinase

et al. 2016

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Background: Germline knockout mice are invaluable in understanding the function of the targeted genes. Sometimes, however, unexpected phenotypes are encountered, due in part to the activation of compensatory mechanisms. Germline ablation of cardiac myosin light chain kinase (cMLCK) causes mild cardiac dysfunction with cardiomyocyte hypertrophy, whereas ablation in adult hearts results in acute heart failure with cardiomyocyte atrophy. We hypothesized that compensation after ablation of cMLCK is dependent on developmental staging and perinatal-onset of cMLCK ablation will result in more evident heart failure than germline ablation, but less profound when compared to adult-onset ablation.Methods and Results: The floxed-Mylk3 gene was ablated at the beginning of the perinatal stage using a single intra-peritoneal tamoxifen injection of 50 mg/kg into pregnant mice on the 19th day of gestation, this being the final day of gestation. The level of cMLCK protein level could no longer be detected 3 days after the injection, with these mice hereafter denoted as the perinatal Mylk3-KO. At postnatal day 19, shortly before weaning age, these mice showed reduced cardiac contractility with a fractional shortening 22.8 ± 1.0% (n = 7) as opposed to 31.4 ± 1.0% (n = 11) in controls. The ratio of the heart weight relative to body weight was significantly increased at 6.68 ± 0.28 mg/g (n = 12) relative to the two control groups, 5.90 ± 0.16 (flox/flox, n = 11) and 5.81 ± 0.33 (wild/wild/Cre, n = 5), accompanied by reduced body weight. Furthermore, their cardiomyocytes were elongated without thickening, with a long-axis of 101.8 ± 2.4 μm (n = 320) as opposed to 87.1 ± 1.6 μm (n = 360) in the controls.Conclusion: Perinatal ablation of cMLCK produces an increase of heart weight/body weight ratio, a reduction of contractility, and an increase in the expression of fetal genes. The perinatal Mylk3-KO cardiomyocytes were elongated in the absence of thickening, differing from the compensatory hypertrophy shown in the germline knockout, and the cardomyocyte thinning shown in adult-inducible knockout.

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“…This adverse effect on heart function was attenuated by cMLCK overexpression in the absence of increased loading. Similarly, Massengill et al (2016) reported that an acute, inducible reduction of cMLCK leads to sarcomeric disorganization, fibrosis, reduced contractility and cell death, and causes severe systolic and diastolic dysfunction and rapid progression to heart failure with reduction of fractional shortening. In addition, Mylk3-KO mouse hearts, lacking expression of cMLCK, displayed a significant reduction in Ca 2+ amplitude and Ca 2+ decay rates as well as SERCA2a mRNA, implying impaired calcium handling (Massengill et al 2016).…”

Section: Introductionmentioning

confidence: 94%

Pseudophosphorylation of cardiac myosin regulatory light chain: a promising new tool for treatment of cardiomyopathy

Yadav

Szczesna‐Cordary

2017

Biophys Rev

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Many genetic mutations in sarcomeric proteins, including the cardiac myosin regulatory light chain (RLC) encoded by the MYL2 gene, have been implicated in familial cardiomyopathies. Yet, the molecular mechanisms by which these mutant proteins regulate cardiac muscle mechanics in health and disease remain poorly understood. Evidence has been accumulating that RLC phosphorylation has an influential role in striated muscle contraction and, in addition to the conventional modulation via Ca 2+ binding to troponin C, it can regulate cardiac muscle function. In this review, we focus on RLC mutations that have been reported to cause cardiomyopathy phenotypes via compromised RLC phosphorylation and elaborate on pseudo-phosphorylation rescue mechanisms. This new methodology has been discussed as an emerging exploratory tool to understand the role of phosphorylation as well as a genetic modality to prevent/rescue cardiomyopathy phenotypes. Finally, we summarize structural effects postphosphorylation, a phenomenon that leads to an ordered shift in the myosin S1 and RLC conformational equilibrium between two distinct states.

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Acute heart failure with cardiomyocyte atrophy induced in adult mice by ablation of cardiac myosin light chain kinase

Abstract: Our results, using a new mouse model mimicking an acute reduction of cMLCK, suggest that cMLCK plays a pivotal role in the transition from compensated to decompensated hypertrophy via sarcomeric disorganization.

Cited by 32 publications

References 47 publications

Lycium barbarum polysaccharides restore adverse structural remodelling and cardiac contractile dysfunction induced by overexpression of microRNA‐1

Lycium barbarum polysaccharides restore adverse structural remodelling and cardiac contractile dysfunction induced by overexpression of microRNA‐1

Heart Failure Induced by Perinatal Ablation of Cardiac Myosin Light Chain Kinase

Pseudophosphorylation of cardiac myosin regulatory light chain: a promising new tool for treatment of cardiomyopathy

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