Chymase-Dependent Conversion of Big Endothelin-1 in the Mouse in Vivo

Simard, Elie; Jin, Denan; Miyazaki, Mizuo; Brochu, Isabelle; D’Orléans-Juste, Pedro

doi:10.1124/jpet.108.142992

Cited by 37 publications

(32 citation statements)

References 40 publications

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“…These results are concordant with previously reported data from our laboratory showing that a chymase inhibitor, Suc-Val-Pro-Phe P (OPh) 2 , inhibited by over 60% the pressor response of Big ET-1 and reduced the plasma level increases of ET-1 by close to 90% in WT mice in vivo (Simard et al, 2009). Although this does not prove conclusively of a more important role of chymase versus ECE .…”

Section: Discussionsupporting

confidence: 81%

“…Specific ECE inhibition with CGS 35066 reduced the pressor response to Big ET-1 in a similar fashion in both groups and further inhibited the residual response to the 38 amino acid precursor in mMCP-4(2/2) mice, whereas both groups responded equally to ET-1 (1-31) administration. Our group previously showed the dual contribution of both chymase and NEP in the in vivo conversion of Big-ET-1 to ET-1 in WT mice (Simard et al, 2009). …”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, Mawatari et al (2004) reported high concentrations of ET-1 (1-31) in the atheromas of atherosclerotic patients. More recently, our laboratory demonstrated that specific chymase inhibition markedly reduces the synthesis of ET-1 from exogenous Big-ET-1 in the mouse model in vivo (Simard et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Pivotal Role of Mouse Mast Cell Protease 4 in the Conversion and Pressor Properties of Big-Endothelin-1

Houde

Jamain

Labonté

et al. 2013

J Pharmacol Exp Ther

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The serine protease chymase has been reported to generate intracardiac angiotensin-II (Ang-II) from Ang-I as well as an intermediate precursor of endothelin-1 (ET-1), ET-1 (1-31) from Big-ET-1. Although humans possess only one chymase, several murine isoforms are documented, each with its own specific catalytic activity. Among these, mouse mast cell protease 4 (mMCP-4) is the isoform most similar to the human chymase for its activity. The aim of this study was to characterize the capacity of mMCP-4 to convert Big-ET-1 into its bioactive metabolite, ET-1, in vitro and in vivo in the mouse model. Basal mean arterial pressure did not differ between wild-type (WT) and mMCP-4(2/2) mice. Systemic administration of Big-ET-1 triggered pressor responses and increased blood levels of immunoreactive (IR) ET-1 (1-31) and ET-1 that were reduced by more than 50% in mMCP-4 knockout (2/2) mice compared with WT controls.Residual responses to Big-ET-1 in mMCP-4(2/2) mice were insensitive to the enkephalinase/neutral endopeptidase inhibitor thiorphan and the specific chymase inhibitor TY-51469 {2-[4-(5-fluoro-3-methylbenzo[b]thiophen-2-yl)sulfonamido-3-methanesulfonylphenyl]thiazole-4-carboxylic acid}. Soluble fractions from the lungs, left cardiac ventricle, aorta, and kidneys of WT but not mMCP-4(2/2) mice generated ET-1 (1-31) from exogenous Big-ET-1 in a TY-51469-sensitive fashion as detected by high-performance liquid chromatography/ matrix-assisted laser desorption/ionization-mass spectrometry. Finally, pulmonary endogenous levels of IR-ET-1 were reduced by more than 40% in tissues derived from mMCP-4(2/2) mice compared with WT mice. Our results show that mMCP-4 plays a pivotal role in the dynamic conversion of systemic Big-ET-1 to ET-1 in the mouse model.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

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Pivotal Role of Mouse Mast Cell Protease 4 in the Conversion and Pressor Properties of Big-Endothelin-1

Houde

Jamain

Labonté

et al. 2013

J Pharmacol Exp Ther

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“…Therefore, mechanisms other than the renin-angiotensin-aldosterone system, such as endothelin, should be considered because mouse or human chymase can process big endothelin to active endothelin-(1-21) (39,43). In addition, it has been previously reported that HS loading in Dahl saltsensitive rats increases blood pressure and renal endothelin expression, which are reversed by an endothelin receptor blocker (17).…”

mentioning

confidence: 99%

Depressor effect of chymase inhibitor in mice with high salt-induced moderate hypertension

Devarajan

Yahiro

Uehara

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Devarajan S, Yahiro E, Uehara Y, Habe S, Nishiyama A, Miura S, Saku K, Urata H. Depressor effect of chymase inhibitor in mice with high salt-induced moderate hypertension. Am J Physiol Heart Circ Physiol 309: H1987-H1996, 2015. First published October 2, 2015; doi:10.1152/ajpheart.00721.2014.-The aim of the present study was to determine whether long-term high salt intake in the drinking water induces hypertension in wild-type (WT) mice and whether a chymase inhibitor or other antihypertensive drugs could reverse the increase of blood pressure. Eight-week-old male WT mice were supplied with drinking water containing 2% salt for 12 wk (high-salt group) or high-salt drinking water plus an oral chymase inhibitor (TPC-806) at four different doses (25, 50, 75, or 100 mg/kg), captopril (75 mg/kg), losartan (100 mg/kg), hydrochlorothiazide (3 mg/kg), eplerenone (200 mg/kg), or amlodipine (6 mg/kg). Control groups were given normal water with or without the chymase inhibitor. Blood pressure and heart rate gradually showed a significant increase in the high-salt group, whereas a dose-dependent depressor effect of the chymase inhibitor was observed. There was also partial improvement of hypertension in the losartan-and eplerenone-treated groups but not in the captopril-, hydrochlorothiazide-, and amlodipine-treated groups. A high salt load significantly increased chymasedependent ANG II-forming activity in the alimentary tract. In addition, the relative contribution of chymase to ANG II formation, but not actual average activity, showed a significant increase in skin and skeletal muscle, whereas angiotensin-converting enzyme-dependent ANG II-forming activity and its relative contribution were reduced by high salt intake. Plasma and urinary renin-angiotensin system components were significantly increased in the high-salt group but were significantly suppressed in the chymase inhibitor-treated group. In conclusion, 2% salt water drinking for 12 wk caused moderate hypertension and activated the renin-angiotensin system in WT mice. A chymase inhibitor suppressed both the elevation of blood pressure and heart rate, indicating a definite involvement of chymase in salt-sensitive hypertension. mouse; high salt; hypertension; renin-angiotensin system; chymase inhibitor NEW & NOTEWORTHYOur study, for the first time, has provided 1) a new establishment of the salt-sensitive hypertensive mice model, 2) confirmation of direct involvement of chymase-mediated mechanisms proved using a specific chymase inhibitor, and 3) the inhibition of all renin-angiotensin-aldosterone components by a chymase inhibitor.THE ASSOCIATION between high salt (HS) intake and elevated blood pressure has been well established by cross-sectional and longitudinal epidemiological studies. Observational studies and clinical trials performed in the general population have indicated that a higher or lower salt intake is associated with an increase or a decrease of blood pressure, respectively (20, 32). However, the response of blood pressure to changes in salt intake...

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“…In a separate group of vessels, the endothelium was mechanically removed, and vessels were subsequently exposed to ET (10 Ϫ9 to 10 Ϫ7 M) (n ϭ 6) and to Big ET (10 Ϫ8 to 10 Ϫ6 M) in the absence (n ϭ 7) and presence (n ϭ 6) of 8-Br-cGMP (100 M). Based on in vivo (7) and in vitro (35,43) observations, we selected a higher dose range of Big ET than ET to achieve similar vasoconstrictor responses. Big ET has no direct vasomotor effect (34), so that the Big ET-induced vasoconstriction reflects the conversion from Big ET to vasoactive ET (7).…”

Section: Myograph Studies Of Isolated Coronary Small Arteriesmentioning

confidence: 99%

Phosphodiesterase-5 activity exerts a coronary vasoconstrictor influence in awake swine that is mediated in part via an increase in endothelin production

Zhou

Beer

Bender

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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Zhou Z, de Beer VJ, Bender SB, Danser AH, Merkus D, Laughlin MH, Duncker DJ. Phosphodiesterase-5 activity exerts a coronary vasoconstrictor influence in awake swine that is mediated in part via an increase in endothelin production. Am J Physiol Heart Circ Physiol 306: H918 -H927, 2014. First published January 24, 2014; doi:10.1152/ajpheart.00331.2013.-Nitric oxide (NO)-induced coronary vasodilation is mediated through production of cyclic guanosine monophosphate (cGMP) and through inhibition of the endothelin-1 (ET) system. We previously demonstrated that phosphodiesterase-5 (PDE5)-mediated cGMP breakdown and ET each exert a vasoconstrictor influence on coronary resistance vessels. However, little is known about the integrated control of coronary resistance vessel tone by these two vasoconstrictor mechanisms. In the present study, we investigated the contribution of PDE5 and ET to the regulation of coronary resistance vessel tone in swine both in vivo, at rest and during graded treadmill exercise, and in vitro. ETA/ETB receptor blockade with tezosentan (3 mg/kg iv) and PDE5 inhibition with EMD360527 (300 g·min Ϫ1 ·kg Ϫ1 iv) each produced coronary vasodilation at rest and during exercise as well as in preconstricted isolated coronary small arteries. In contrast, tezosentan failed to produce further coronary vasodilation in the presence of EMD360527, both in vivo and in vitro. Importantly, EMD360527 (3 M) and cGMP analog 8-Br-cGMP (100 M) had no significant effects on ET-induced contractions of isolated porcine coronary small arteries, suggesting unperturbed ET receptor responsiveness. In contrast, PDE5 inhibition and cGMP blunted the contractions produced by the ET precursor Big ET, but only in vessels with intact endothelium, suggesting that PDE5 inhibition limited ET production in the endothelium of small coronary arteries. In conclusion, PDE5 activity exerts a vasoconstrictor influence on coronary resistance vessels that is mediated, in part, via an increase in endothelial ET production. PDE5 inhibition; ETA/ETB blockade; ET; Big ET; coronary vasomotor tone CORONARY BLOOD FLOW IS TIGHTLY coupled to myocardial oxygen demand to maintain a consistently high level of myocardial oxygen extraction (10,16,26). This tight coupling has been proposed to depend on a myriad of vasodilators and vasoconstrictors, including nitric oxide (NO) and endothelin-1 (ET). NO causes coronary vasodilation by stimulating guanylyl cyclase in vascular smooth muscle to generate cyclic guanosine monophosphate (cGMP), which activates cGMP-dependent protein kinase G (PKG) (32). Levels of cGMP in vascular smooth muscle are tightly regulated by several cyclic nucleotide phosphodiesterases (PDEs) that hydrolyze cGMP and terminate its vasodilator effect (2). PDE5 is present in vascular smooth muscle cells in the coronary vascular bed and thus has the potential to regulate coronary blood flow by exerting a vasoconstrictor influence. Indeed, PDE5 inhibition resulted in relaxation of coronary conduit arteries in swine in vitro (45) and in vivo (1),...

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Chymase-Dependent Conversion of Big Endothelin-1 in the Mouse in Vivo

Cited by 37 publications

References 40 publications

Pivotal Role of Mouse Mast Cell Protease 4 in the Conversion and Pressor Properties of Big-Endothelin-1

Pivotal Role of Mouse Mast Cell Protease 4 in the Conversion and Pressor Properties of Big-Endothelin-1

Depressor effect of chymase inhibitor in mice with high salt-induced moderate hypertension

Phosphodiesterase-5 activity exerts a coronary vasoconstrictor influence in awake swine that is mediated in part via an increase in endothelin production

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