Chymase Plays an Important Role in Left Ventricular Remodeling Induced by Intermittent Hypoxia in Mice

Matsumoto, Chika; Hayashi, Toshio; Kitada, Kento; Yamashita, Chika; Miyamura, Masatoshi; Mori, Tatsuhiko; Ukimura, Akira; Ohkita, Mamoru; Jin, Denan; Takai, Shinji; Miyazaki, Mizuo; Okada, Yoshinori; Kitaura, Yasushi; Matsumura, Yasuo

doi:10.1161/hypertensionaha.109.131391

Cited by 39 publications

(30 citation statements)

References 53 publications

(53 reference statements)

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“…Chymase inhibitors are also effective in models for myocardial infarction, 102,103 intimal hyperplasia after balloon injury, 104 Big endothelin-1 conversion, 105 and ventricular remodeling induced by intermittent hypoxia. 106 In addition, chymase inhibitors have anti-inflammatory functions, for example, by reducing the eosinophilia during N brasiliensis infection 107 and by preventing eosinophil accumulation in a model for atopic dermatitis. 108 Together, this development strongly implicates chymase as a promising therapeutic target in variety of clinical settings, and we anticipate that this notion will be evaluated through clinical trials in the near future.…”

Section: Chymase Inhibitorsmentioning

confidence: 99%

Mast cell proteases: multifaceted regulators of inflammatory disease

Pejler

Rönnberg

Waern

et al. 2010

Blood

332

296

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IntroductionMast cells (MCs) are still mainly known for their harmful effects in connection with allergic reactions. However, this simplistic view is currently being extensively modified, and it is becoming more and more established that MCs have a complex array of functions and can contribute to a number of additional disorders. 1 In addition to being detrimental, MCs also carry out a number of beneficial functions, most notably in connection with innate immune responses toward various pathogens. 2 Moreover, recent studies indicate that MCs can play important roles in down-regulating adaptive immune responses. 3,4 As a consequence of this progress, MCs are gaining a massively increased interest worldwide, and much effort is invested into investigations of the mechanisms by which MCs contribute to different disorders.A striking morphologic feature of MCs is their abundance of electron-dense secretory granules, which contain large amounts of preformed compounds commonly referred to as "MC mediators." These include biogenic amines (histamine and serotonin), certain preformed cytokines (most notably tumor necrosis factor), serglycin proteoglycans, various lysosomal enzymes, and a number of MC-specific proteases of chymase, tryptase, or carboxypeptidase A (MC-CPA) type. [5][6][7][8] When MCs are induced to undergo degranulation, for example, through engagement of Fc⑀RI-bound IgE by polyvalent antigen, these mediators are thus released. 9 The MC proteases are expressed at exceptionally high levels, with mRNA levels approaching and even exceeding those of classic housekeeping genes, 10 and they are stored in remarkably high amounts. Indeed, it has been calculated that MC proteases may account for more than 25% of the total MC protein. 11,12 Importantly, in contrast to, for example, the pancreatic digestive proteases, the MC proteases are stored in fully active form; and when MCs undergo degranulation, large amounts of enzymatically active proteases are thus released into the extracellular space and probably have a profound impact on any condition in which MC degranulation occurs (Figure 1). Indeed, a plethora of potential functions of the MC proteases have previously been outlined, based on various approaches. 6 However, it is not until relatively recently that the in vivo functions of these enzymes have started to become unraveled through experimental approaches involving MC proteasedeficient mice. In this review, we summarize these findings and discuss their implications. Substrate specificity, distribution, and storageThe term "MC proteases" usually refers to the proteases that are expressed specifically by MCs and are stored in their secretory granules, that is, chymases, tryptases, and MC-CPA. However, it should be pointed out that MCs express a number of additional, non-MC-specific, proteases, such as lysosomal cathepsins, granzymes, neurolysin, and, possibly, cathepsin G. 6 Recently, the strictly MC-specific expression of the chymases has been used to generate mouse strains in which the Cre recombinase is expre...

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Section: Chymase Inhibitorsmentioning

confidence: 99%

Mast cell proteases: multifaceted regulators of inflammatory disease

Pejler

Rönnberg

Waern

et al. 2010

Blood

332

296

View full text Add to dashboard Cite

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“…The fibrotic area in the cardiac tissues and the mRNA levels of collagen I and collagen III were also significantly lower in the chymase inhibitor-treated group. Recently, we also demonstrated that cardiac fibrotic areas under intermittent hypoxia were also significantly attenuated by treatment with a chymase inhibitor in rats (57). Therefore, the pathway forming chymase-dependent TGF-β may play an important role in myocardial fibrosis and cardiac dysfunction after myocardial infarction.…”

Section: Cardiac Dysfunction and Fibrosismentioning

confidence: 88%

New Approaches to Blockade of the Renin–Angiotensin–Aldosterone System: Chymase as an Important Target to Prevent Organ Damage

2010

Self Cite

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Abstract. Chymase plays a crucial role in angiotensin II formation in various tissues. Angiotensin II induces gene expression of transforming growth factor (TGF)-β and matrix metalloproteinase (MMP)-9 precursors, and chymase can convert precursors of TGF-β and MMP-9 to their active forms. In cultured fibroblasts, significant increases in cell growth and TGF-β levels were observed after chymase injection; these increases were inhibited by a chymase inhibitor, but not by an angiotensin II-receptor blocker. In apolipoprotein E-deficient mice, abdominal aortic aneurysm (AAA) development depends on an increase in MMP-9 activities induced by angiotensin II infusion, but the inhibition of MMP-9 activation by a chymase inhibitor resulted in attenuation of the angiotensin II-induced AAA development. The upregulation of MMP-9 and TGF-β levels is involved in damage to various organs, but these gene expressions are not completely induced by angiotensin II alone. Therefore, chymase inhibition may be useful for attenuating MMP-9 and TGF-β levels, in addition to reducing angiotensin II formation, and this function may provide powerful organ protection. In this review, we propose the possible use of chymase inhibitors as agents to prevent organ damage.

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“…The deleterious effect of unopposed Chymase activity was associated with poor clinical outcome [32]. In a pre-clinical study, Chymase was able to induce hypoxia in myocardium leading to remodeling of cardiac architecture independent of blood pressure [33] although this has not been firmly established in humans. Acute myocardial infarction resulting from sudden occlusion of the coronary artery is dependent on sudden rupture of the atheroma cap.…”

Section: Distribution and Activity Of Chymase In Cardiac Tissuementioning

confidence: 99%

A Review on the Role of Chymase in Hypertensive Heart Disease

Boamah¹,

Armah²

2017

IJPHC

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Hypertensive heart disease is the commonest cardiac complication resulting from longstanding hypertension. Hypertensive patients inevitably develop hypertensive heart disease but the intensity and progression vary. Poor control is associated with a fast progression and worse outcome while the outcome of adequately controlled blood pressure is antithetical to the former. Various biochemical mediators have been implicated in hypertension and its related complications. Angiotensin-II is involved in both hypertension and remodeling of the cardiac and vascular architecture. The focus on Chymase and its inhibitors in modulating angiotensin-II levels have cast some doubts on the efficacy of solely using angiotensin converting enzyme inhibitors.

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Chymase Plays an Important Role in Left Ventricular Remodeling Induced by Intermittent Hypoxia in Mice

Cited by 39 publications

References 53 publications

Mast cell proteases: multifaceted regulators of inflammatory disease

Mast cell proteases: multifaceted regulators of inflammatory disease

New Approaches to Blockade of the Renin–Angiotensin–Aldosterone System: Chymase as an Important Target to Prevent Organ Damage

A Review on the Role of Chymase in Hypertensive Heart Disease

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