Calpain-dependent Cleavage of N-cadherin Is Involved in the Progression of Post-myocardial Infarction Remodeling

Kudo-Sakamoto, Yoko; Akazawa, Hiroshi; Ito, Kei; Takano, Jiro; Yano, Masamichi; Yabumoto, Chizuru; Naito, Atsuhiko T.; Oka, Tôru; Lee, Jong-Kook; Sakata, Yasushi; Suzuki, Jun–ichi; Saido, Takaomi C.; Komuro, Issei

doi:10.1074/jbc.m114.567206

Cited by 42 publications

(41 citation statements)

References 54 publications

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“…10 Myocardial calpain plays an essential role in the ubiquitin/proteasome protein degradation pathway that removes proteins whose abnormal accumulation causes cardiomyocyte apoptosis and heart failure. 11 , 12 In ischemic heart disease, calpain activation has been found to promote left ventricular remodeling after myocardial infarction by disassembling cell-cell adhesion via degradation of N-cadherin.…”

Section: Introductionmentioning

confidence: 99%

“…11 , 12 In ischemic heart disease, calpain activation has been found to promote left ventricular remodeling after myocardial infarction by disassembling cell-cell adhesion via degradation of N-cadherin. 10 However, uncontrolled activation of calpain has been proven to be involved in the pathogenesis of myocardial ischemia and dysfunction. 13 Similarly, in metabolic syndrome, hyper activation of calpain has been linked to myocardial and vascular inflammation and impaired collateral formation.…”

Section: Introductionmentioning

confidence: 99%

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Calpain inhibition decreases myocardial apoptosis in a swine model of chronic myocardial ischemia

Potz

Sabe

Elmadhun

et al. 2015

Surgery

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Introduction Calpain is a family of cysteine proteases that has an important role in the initiation, regulation and execution of cell death. Our recent studies using a hypercholesterolemic swine model demonstrated that in the setting of metabolic syndrome calpain inhibition improved collateral dependent perfusion, and increased expression of proteins implicated in angiogenesis and vasodilation. In this study, we hypothesized that calpain inhibition (CI) would decrease myocardial apoptosis in the same model. Methods Yorkshire swine, fed a high cholesterol diet for four weeks, then underwent placement of an ameroid constrictor on the left circumflex artery. Three weeks later animals received either: no drug, high cholesterol control group (HCC; n= 8); low dose CI (0.12 mg/kg; LCI, n= 9); or high dose CI (0.25 mg/kg; HCI, n= 8). The high cholesterol diet and CI were continued for five weeks, after which the pig was euthanized and the left ventricular myocardium was harvested and analyzed via TUNEL staining, oxyblot analysis and western blots. Data was analyzed via the Kruskal-Wallis test. Results The percentage of apoptotic cells to total cells in ischemic myocardial territory was significantly decreased in the LCI and HCI groups compared to the HCC group as shown by TUNEL staining (p= 0.018). There was a significant decrease in pro-apoptotic proteins including cleaved caspase 3 (p =0.001), caspase 9 (p = 0.003), cleaved caspase 9 (p=0.004), Bax (p=0.0262), BAD (p= 0.049), p-BAD (p= 0.007) , Erk 1/2 (p= 0.016) and a statistically insignificant decrease in caspase 3 (p= 0.737). There was a significant increase in anti-apoptotic proteins including BCL-2 (p= 0.025) and p-BCL2 (p= 0.004). In the ischemic myocardium, there was a significant increase in several pro-angiogenic proteins in the LCI and HCI groups compared to the HCC group including p-AKT (p=0.0001), p-eNOS (p= 0.003) and eNOS (p=0.006) with a statistically insignificant increase seen in AKT (p=0.311). CI significantly decreased tissue oxidative stress in both the LCI and HCI groups as compared to the HCC group as shown by Oxyblot analysis (p= 0.021). Conclusions In the setting of hypercholesterolemia, CI decreases apoptosis and the expression of proteins in pro apoptotic signaling pathways. CI also increased expression of proteins implicated anti apoptotic pathways and improves oxidative stress in ischemic myocardial tissue.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Calpain inhibition decreases myocardial apoptosis in a swine model of chronic myocardial ischemia

Potz

Sabe

Elmadhun

et al. 2015

Surgery

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“…N-cadherin expression and localization at cell-cell contacts is associated with increased stability of β-catenin and decreased expression of α-SMA (Xu et al, 2012). CFs form N-cadherin-mediated interactions with CMs, which influences CM structure and contractility during development, normal function and disease (Chopra et al, 2011;Kudo-Sakamoto et al, 2014;Vreeker et al, 2014). In a recent study, N-cadherin bonds between CFs and CMs were shown to dynamically deform CM membranes in response to MyoFB contraction and induce a measurable slowing of CM conduction velocity (Thompson et al, 2014).…”

Section: Cadherins Sense Intercellular Forcesmentioning

confidence: 99%

Mechanobiology of myofibroblast adhesion in fibrotic cardiac disease

Schroer

Merryman

2015

Journal of Cell Science

117

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Fibrotic cardiac disease, a leading cause of death worldwide, manifests as substantial loss of function following maladaptive tissue remodeling. Fibrosis can affect both the heart valves and the myocardium and is characterized by the activation of fibroblasts and accumulation of extracellular matrix. Valvular interstitial cells and cardiac fibroblasts, the cell types responsible for maintenance of cardiac extracellular matrix, are sensitive to changing mechanical environments, and their ability to sense and respond to mechanical forces determines both normal development and the progression of disease. Recent studies have uncovered specific adhesion proteins and mechano-sensitive signaling pathways that contribute to the progression of fibrosis. Integrins form adhesions with the extracellular matrix, and respond to changes in substrate stiffness and extracellular matrix composition. Cadherins mechanically link neighboring cells and are likely to contribute to fibrotic disease propagation. Finally, transition to the active myofibroblast phenotype leads to maladaptive tissue remodeling and enhanced mechanotransductive signaling, forming a positive feedback loop that contributes to heart failure. This Commentary summarizes recent findings on the role of mechanotransduction through integrins and cadherins to perpetuate mechanically induced differentiation and fibrosis in the context of cardiac disease.

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“…Very few studies describe the role of microRNA regulation of calpains. Kudo-Sakamoto [15] described the effects of calpain on calpastatin-deficient mice. Analysis of calpastatin-deficient mice in comparison with wild type revealed a significant reduction in the survival rate.…”

Section: Heart Failure Calpainsmentioning

confidence: 99%

Resuscitation of a dead cardiomyocyte

2015

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Although cardiac resuscitation can revive the whole body, the mechanisms are unclear. To this end, we propose that reviving a dead/dysfunctional cardiomyocyte will shed light on resuscitation mechanisms and pave the way to treat cardiac myopathies. The degradation of the myocyte cytoskeleton by the proteasome system which involves calpains, ubiquitin, caspases and matrix metalloproteases is the main focus of this review. The activation of calpains beyond the calpastatin-mediated inhibition due to extensive calcium harbor can lead to titin degradation, damage to the sarcomere and contractile dysfunction. The ubiquitin proteasome system can disturb the protein homeostasis within the cell and generate a dysfunctional myocyte. The matrix metalloproteases disrupt the collagen/elastin ratio and connexins to generate arrhythmias. The concept of cardiac resuscitation stems from protecting the myocyte cytoskeleton and keeping the protein homeostasis intact through management of the degradation machinery. In this regard, proteasome inhibitors for the degradation machinery have an elegant space. Recently exosomes have been identified potentially, as carriers of microRNAs or proteins that can modify the target cells. Exosomes loaded with the inhibitor "cargo" which comprises microRNAs, siRNAs or proteins to inhibit the degradation machinery can be a method of choice for cardiac resuscitation-a process difficult to execute.

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Calpain-dependent Cleavage of N-cadherin Is Involved in the Progression of Post-myocardial Infarction Remodeling

Cited by 42 publications

References 54 publications

Calpain inhibition decreases myocardial apoptosis in a swine model of chronic myocardial ischemia

Calpain inhibition decreases myocardial apoptosis in a swine model of chronic myocardial ischemia

Mechanobiology of myofibroblast adhesion in fibrotic cardiac disease

Resuscitation of a dead cardiomyocyte

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