Role For Chymase in Heart Failure

Kokkonen, Jorma; Lindstedt, Ken A.; Kovanen, Petri T.

doi:10.1161/01.cir.0000074786.92067.aa

Cited by 37 publications

(7 citation statements)

References 27 publications

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“…On the other hand, there are endogenous protease inhibitors in the interstitial fluid that would inhibit chymase activity. 35 The importance of proteolytic activity for the wall stress-induced maladaptive venous remodelling has been highlighted by a recent study; inhibition of the 26S proteasome using bortezomib led to a stabilization of the quiescent SMC phenotype. Bortezomib inhibits the chymotrypsin-like activity of the 26S proteasome, and transdermal administration diminished venous SMC proliferation by 80% and inhibited varicose-like venous remodelling in a mouse model.…”

Section: Discussionmentioning

confidence: 99%

Extracellular matrix remodelling in response to venous hypertension: proteomics of human varicose veins

et al. 2016

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AimsExtracellular matrix remodelling has been implicated in a number of vascular conditions, including venous hypertension and varicose veins. However, to date, no systematic analysis of matrix remodelling in human veins has been performed.Methods and resultsTo understand the consequences of venous hypertension, normal and varicose veins were evaluated using proteomics approaches targeting the extracellular matrix. Varicose saphenous veins removed during phlebectomy and normal saphenous veins obtained during coronary artery bypass surgery were collected for proteomics analysis. Extracellular matrix proteins were enriched from venous tissues. The proteomics analysis revealed the presence of >150 extracellular matrix proteins, of which 48 had not been previously detected in venous tissue. Extracellular matrix remodelling in varicose veins was characterized by a loss of aggrecan and several small leucine-rich proteoglycans and a compensatory increase in collagen I and laminins. Gene expression analysis of the same tissues suggested that the remodelling process associated with venous hypertension predominantly occurs at the protein rather than the transcript level. The loss of aggrecan in varicose veins was paralleled by a reduced expression of aggrecanases. Chymase and tryptase β1 were among the up-regulated proteases. The effect of these serine proteases on the venous extracellular matrix was further explored by incubating normal saphenous veins with recombinant enzymes. Proteomics analysis revealed extensive extracellular matrix degradation after digestion with tryptase β1. In comparison, chymase was less potent and degraded predominantly basement membrane-associated proteins.ConclusionThe present proteomics study provides unprecedented insights into the expression and degradation of structural and regulatory components of the vascular extracellular matrix in varicosis.

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Section: Discussionmentioning

confidence: 99%

Extracellular matrix remodelling in response to venous hypertension: proteomics of human varicose veins

et al. 2016

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“…Mast cell-derived chymase has been recognized as an important factor in the formation of ANG II in the heart [69,70,84–88]. Thus, the potential use of chymase inhibitors to delay the evolution of heart failure has been advocated [82,89]. Indeed, chymase inhibition prevents cardiac fibrosis and improves diastolic dysfunction in the progression of heart failure [90].…”

Section: Mast Cell-derived Renin and Activation Of At1r On Sympathetimentioning

confidence: 99%

Targeting Cardiac Mast Cells: Pharmacological Modulation of the Local Renin-Angiotensin System

Reid¹,

Brazin²,

Morrey³

et al. 2011

CPD

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Enhanced production of angiotensin II and excessive release of norepinephrine in the ischemic heart are major causes of arrhythmias and sudden cardiac death. Mast cell-dependent mechanisms are pivotal in the local formation of angiotensin II and modulation of norepinephrine release in cardiac pathophysiology. Cardiac mast cells increase in number in myocardial ischemia and are located in close proximity to sympathetic neurons expressing angiotensin AT1- and histamine H3-receptors. Once activated, cardiac mast cells release a host of potent pro-inflammatory and pro-fibrotic cytokines, chemokines, preformed mediators (e.g., histamine) and proteases (e.g., renin). In myocardial ischemia, angiotensin II (formed locally from mast cell-derived renin) and histamine (also released from local mast cells) respectively activate AT1- and H3-receptors on sympathetic nerve endings. Stimulation of angiotensin AT1-receptors is arrhythmogenic whereas H3-receptor activation is cardioprotective. It is likely that in ischemia/reperfusion the balance may be tipped toward the deleterious effects of mast cell renin, as demonstrated in mast cell-deficient mice, lacking mast cell renin and histamine in the heart. In these mice, no ventricular fibrillation occurs at reperfusion following ischemia, as opposed to wild-type hearts which all fibrillate. Preventing mast cell degranulation in the heart and inhibiting the activation of a local reninangiotensin system, hence abolishing its detrimental effects on cardiac rhythmicity, appears to be more significant than the loss of histamine-induced cardioprotection. This suggests that therapeutic targets in the treatment of myocardial ischemia, and potentially congestive heart failure and hypertension, should include prevention of mast cell degranulation, mast cell renin inhibition, local ACE inhibition, ANG II antagonism and H3-receptor activation.

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“…However, chymase can also induce activation of TGF-β, a major regulator of tissue fibrosis, and matrix metalloproteinase (MMP)-9 activity which seems to be implicated in inflammatory processes independent of the RAS 45 . Although, we may still be far from understanding the exact cellular and molecular mechanisms by which chymase participates in the progression of organ failure, specific chymase inhibitors may emerge as an important tool for defining the role of mast cells and chymase in the pathophysiology of graft damage 46 . Recent data showing that intrarenal Ang II production and the development of hypertension are prevented by selective chymase inhibition support our results of a central contribution of chymase to local allograft Ang II formation 47 .…”

Section: Discussionmentioning

confidence: 99%

Intrarenal Renin-Angiotensin-System Dysregulation after Kidney Transplantation

Kovarík

Kaltenecker

Kopecky

et al. 2019

Sci Rep

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Angiotensin-converting enzyme inhibitors (ACEis) are beneficial in patients with chronic kidney disease (CKD). Yet, their clinical effects after kidney transplantation (KTx) remain ambiguous and local renin-angiotensin system (RAS) regulation including the ‘classical’ and ‘alternative’ RAS has not been studied so far. Here, we investigated both systemic and kidney allograft-specific intrarenal RAS using tandem mass-spectrometry in KTx recipients with or without established ACEi therapy (n = 48). Transplant patients were grouped into early (<2 years), intermediate (2–12 years) or late periods after KTx (>12 years). Patients on ACEi displayed lower angiotensin (Ang) II plasma levels ( P < 0.01) and higher levels of Ang I ( P < 0.05) and Ang-(1–7) ( P < 0.05) compared to those without ACEi independent of graft vintage. Substantial intrarenal Ang II synthesis was observed regardless of ACEi therapy. Further, we detected maximal allograft Ang II synthesis in the late transplant vintage group ( P < 0.005) likely as a consequence of increased allograft chymase activity ( P < 0.005). Finally, we could identify neprilysin (NEP) as the central enzyme of ‘alternative RAS’ metabolism in kidney allografts. In summary, a progressive increase of chymase-dependent Ang II synthesis reveals a transplant-specific distortion of RAS regulation after KTx with considerable pathogenic and therapeutic implications.

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Role For Chymase in Heart Failure

Cited by 37 publications

References 27 publications

Extracellular matrix remodelling in response to venous hypertension: proteomics of human varicose veins

Extracellular matrix remodelling in response to venous hypertension: proteomics of human varicose veins

Targeting Cardiac Mast Cells: Pharmacological Modulation of the Local Renin-Angiotensin System

Intrarenal Renin-Angiotensin-System Dysregulation after Kidney Transplantation

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