Dual inhibition of cathepsin G and chymase reduces myocyte death and improves cardiac remodeling after myocardial ischemia reperfusion injury

Hooshdaran, Bahman; Kolpakov, Mikhail A.; Guo, Xinji; Miller, Sonni A.; Wang, Tao; Tilley, Douglas G.; Rafiq, Khadija; Sabri, Abdelkarim

doi:10.1007/s00395-017-0652-z

Cited by 54 publications

(39 citation statements)

References 43 publications

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“…Although cardiac fibrosis is detrimental to long-term heart function, initial matrix deposition is crucial to the initiation of myocardial repair ( Frangogiannis, 2014 ). The direct effect of chymase on myocardial fibroblasts is less clear, as results from Carver and colleagues suggest that chymase reduces cardiac fibroblast production of extracellular matrix and their conversion to the myofibroblast phenotype, while Hooshdaran and collaborators found that chymase and cathepsin G promote differentiation into myofibroblasts, although they did not differentiate between these two close proteases ( Carver et al, 2015 ; Hooshdaran et al, 2017 ). Chymase, together with its activation of MMP-9, is also a direct matrix degrading enzyme and may reduce fibroblast pro-collagen-1 production ( Fu et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Mouse Mast Cell Protease 4 Deletion Protects Heart Function and Survival After Permanent Myocardial Infarction

et al. 2018

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Chymase, a mast cell serine protease involved in the generation of multiple cardiovascular factors, such as angiotensin II and endothelin-1 (ET-1), is elevated and participates in tissue degeneration after permanent myocardial infarction (PMI). Anesthetized 4-month old male wild-type (WT) C57BL/6J mice and mouse mast cell protease-4 knockout (mMCP-4 KO) congeners were subjected to ligation of the left anterior descending (LAD) coronary artery. A group of mice was then subjected to Kaplan-Meier 28-day survival analysis. In another group of mice, 18F-fluorodeoxyglucose positron emission tomography (PET) was performed to evaluate heart function and the infarcted zone 3 days post-PMI surgery. Cardiac morphology following PMI was evaluated on formalin-fixed heart slices and glycoproteomic analysis was performed using mass spectrometry. Finally, cardiac and lung tissue content of immunoreactive ET-1 was determined. PMI caused 60% mortality in WT mice, due to left ventricular wall rupture, and 7% in mMCP-4 KO mice. Cardiac PET analysis revealed a significant reduction in left ventricular volume (systolic and diastolic) and preserved the ejection fraction in mMCP-4 KO compared to WT animals. The infarcted area, apoptotic signaling and wall remodeling were significantly decreased in mMCP-4 KO mice compared to their WT congeners, while collagen deposition was increased. Glycoproteomic analysis showed an increase in apolipoprotein A1, an established chymase substrate in mMCP-4 KO mice compared to WT mice post-PMI. ET-1 levels were increased in the lungs of WT, but not mMCP-4 KO mice, 24 h post-PMI. Thus, the genetic deletion of mMCP-4 improved survival and heart function post-PMI.

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Section: Discussionmentioning

confidence: 99%

Mouse Mast Cell Protease 4 Deletion Protects Heart Function and Survival After Permanent Myocardial Infarction

et al. 2018

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“…Chymase inhibitors (Matsumoto, 2003;Hooshdaran, 2017) None Inhibition of local chymases, PAR-1 activators Experimental drugs Unknown above). The presence of chymase in the heart can therefore limit the efficacy of ACE inhibitors (Wei, 2010).…”

Section: Reduction Of Thrombin Formation (New) Oral Anticoagulantsmentioning

confidence: 99%

“…The experimental chymase inhibitor SUNC8257 partially prevented ventricular remodeling in an animal model of tachycardia-induced heart failure, leading to reduction of diastolic dysfunction and atrial dilatation (Matsumoto, 2003). In a model of cardiac infarction, chymase inhibition prevented myocyte apoptosis and fibroblast migration/differentiation (Hooshdaran, 2017).…”

Section: Reduction Of Thrombin Formation (New) Oral Anticoagulantsmentioning

confidence: 99%

Pharmacological Inhibition of Serine Proteases to Reduce Cardiac Inflammation and Fibrosis in Atrial Fibrillation

et al. 2019

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Systemic inflammation correlates with an increased risk of atrial fibrillation (AF) and thrombogenesis. Systemic inflammation alters vessel permeability, allowing inflammatory and immune cell migration toward target organs, including the heart. Among inflammatory cells infiltrating the atria, macrophages and mast cell have recently attracted the interest of basic researchers due to the pathogenic mechanisms triggered by their activation. This chemotactic invasion is likely implicated in shortand long-term changes in cardiac cell-to-cell communication and in triggering fibrous tissue accumulation in the atrial myocardium and electrophysiological rearrangements of atrial cardiomyocytes, thus favoring the onset and progression of AF. Serine proteases are a large and heterogeneous class of proteases involved in several processes that are important for cardiac function and are involved in cardiac diseases, such as (i) coagulation, (ii) fibrinolysis, (iii) extracellular matrix degradation, (iv) activation of receptors (i.e., protease-activated receptors [PPARs]), and (v) modulation of the activity of endogenous signals. The recognition of serine proteases substrates and their involvement in inflammatory/profibrotic mechanisms allowed the identification of novel cardio-protective mechanisms for commonly used drugs that inhibit serine proteases. The aim of this review is to summarize knowledge on the role of inflammation and fibrosis as determinants of AF. Moreover, we will recapitulate current findings on the role of serine proteases in the pathogenesis of AF and the possible beneficial effects of drugs inhibiting serine proteases in reducing the risk of AF through decrease of cardiac inflammation and fibrosis. These drugs include thrombin and factor Xa inhibitors (used as oral anticoagulants), dipeptidyl-peptidase 4 (DPP4) inhibitors, used for type-2 diabetes, as well as novel experimental inhibitors of mast cell chymases.

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“…Cells were seeded onto a 96-well plate, and the MTT tetrazolium compound was then added to the medium (2 mg/ml; Sigma-Aldrich, St. Louis, MO, USA); the cells were then cultured in the dark for 4 h and then DMSO was added to the medium. The optical density of each well was observed at 490 nm using a spectrophotometer (Epoch 2; BioTek Instruments, Inc., Winooski, VT, USA) [29]. The TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assay was used to detect apoptotic cells.…”

Section: Cell Viability and Tunel Stainingmentioning

confidence: 99%

Mitofusin-2 regulates inflammation-mediated mouse neuroblastoma N2a cells dysfunction and endoplasmic reticulum stress via the Yap-Hippo pathway

2019

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Endoplasmic reticulum (ER) stress is involved in inflammation-induced neurotoxicity. Mitofusin 2 (Mfn2), a member of the GTPase family of proteins, resides in the ER membrane and is known to regulate ER stress. However, the potential role and underlying mechanism of Mfn2 in inflammation-induced neuronal dysfunction is unknown. In our study, we explored the potential of Mfn2 to attenuate inflammation-mediated neuronal dysfunction by inhibiting ER stress. Our data show that Mfn2 overexpression significantly ameliorated tumor necrosis factor alpha (TNFα)-induced ER stress, as indicated by the downregulation of the ER stress proteins PERK, GRP78 and CHOP. Mfn2 overexpression also prevented the TNFα-mediated activation of caspase-3, caspase-12 and cleaved poly (ADP-ribose) polymerase (PARP). Cellular antioxidant dysfunction and reactive oxygen species overproduction were also improved by Mfn2 in the setting of TNFα in mouse neuroblastoma N2a cells in vitro. Similarly, disordered calcium homeostasis, indicated by disturbed levels of calcium-related proteins and calcium overloading, was corrected by Mfn2, as evidenced by the increased expression of store-operated calcium entry (SERCA), decreased levels of inositol trisphosphate receptor (IP3R), and normalized calcium content in TNFα-treated N2a cells. Mfn2 overexpression was found to elevate Yes-associated protein (Yap) expression; knockdown of Yap abolished the regulatory effects of Mfn2 on ER stress, oxidative stress, calcium balance, neural death and inflammatory injury. These results lead us to conclude that re-activation of the Mfn2-Yap signaling pathway alleviates TNFα-induced ER stress and dysfunction of mouse neuroblastoma N2a cells. Our findings provide a better understanding of the regulatory role of Mfn2-Yap-ER stress in neuroinflammation and indicate that the Mfn2-Yap axis may be a focus of research in terms of having therapeutic value for the treatment of neurodegenerative diseases.

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Dual inhibition of cathepsin G and chymase reduces myocyte death and improves cardiac remodeling after myocardial ischemia reperfusion injury

Cited by 54 publications

References 43 publications

Mouse Mast Cell Protease 4 Deletion Protects Heart Function and Survival After Permanent Myocardial Infarction

Mouse Mast Cell Protease 4 Deletion Protects Heart Function and Survival After Permanent Myocardial Infarction

Pharmacological Inhibition of Serine Proteases to Reduce Cardiac Inflammation and Fibrosis in Atrial Fibrillation

Mitofusin-2 regulates inflammation-mediated mouse neuroblastoma N2a cells dysfunction and endoplasmic reticulum stress via the Yap-Hippo pathway

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