Role of Chymase-Dependent Angiotensin II Formation in Monocrotaline-Induced Pulmonary Hypertensive Rats

Kishi, Kazushi; Jin, Denan; Takai, Shinji; Muramatsu, Michiko; Katayama, Hiroshi; Tamai, Hiroshi; Miyazaki, Mizuo

doi:10.1203/01.pdr.0000219431.45075.d9

Cited by 19 publications

(18 citation statements)

References 28 publications

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“…Losartan (10 mg/kg per day) did not inhibit monocrotaline-induced pulmonary hypertension and RV hypertrophy (14). On the other hands, Kishi et al reported that candesartan (10 mg/kg per day) prevented the decrease of AT, the increase of pulmonary arterial pressure, and RV hypertrophy induced by monocrotaline treatment (15). The present study demonstrated that telmisartan did not improve the decrease of AT /ET ratio, but attenuated RV hypertrophy.…”

Section: Discussioncontrasting

confidence: 52%

“…The effects of angiotensin II type 1 receptor (AT1R) blockers in monocrotalineinduced RV hypertrophy have not yet been completely clarified. Losartan did not inhibit monocrotalineinduced RV hypertrophy (14), while candesartan prevented it (15). Telmisartan, a 5th generation AT1R blocker, is used for the treatment of hypertension and has cardioprotective effects (16).…”

Section: Introductionmentioning

confidence: 99%

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Effects of Telmisartan on Right Ventricular Remodeling Induced by Monocrotaline in Rats

et al. 2009

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Abstract. The present study investigated whether telmisartan, an angiotensin II type 1 receptor antagonist, has cardioprotective effects on monocrotaline-induced right ventricular (RV) remodeling in rats. Six-week-old male Wistar rats were divided into control group (CONT), monocrotaline (60 mg/ kg, i.p.)-treated group (MCT), monocrotaline (60 mg/ kg, i.p.) + telmisartan (3 mg/kg per day, p.o.)-treated group (MCT+TEL), and telmisartan (3 mg/kg per day, p.o.) alonetreated group (TEL). Hearts were excised after echocardiography examinations at day 25. Significant increase in RV weight and histologically remarkable fibrosis in RV sections were observed in MCT. Tricuspid annular plane systolic excursion, a parameter for RV systolic function, significantly decreased in MCT. These RV hypertrophy, fibrosis, and dysfunction were inhibited in MCT+TEL. In MCT, the acceleration time/ejection time ratio of pulmonary artery flow velocity, an index of pulmonary hypertension, significantly decreased. This decrease was not affected in MCT+TEL. In MCT, expressions and activities of matrix metalloproteinase (MMP)-2 and MMP-9, which play a critical role in cardiac remodeling, significantly increased in the RV. In MCT+TEL, these increases in expressions and activities were inhibited. MCT showed about 2-fold increase in transforming growth factor-β1 expression compared with CONT, and such an increase was not decreased in MCT+TEL. There were no significant changes of these parameters in TEL compared with CONT. These results suggest that telmisartan could attenuate the monocrotaline-induced RV remodeling through improvements of RV hypertrophy, fibrosis, dysfunction, and inhibition of MMPs.

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Section: Discussioncontrasting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Effects of Telmisartan on Right Ventricular Remodeling Induced by Monocrotaline in Rats

et al. 2009

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“…It has recently been reported that the Ang II generating chymase gene is expressed in rat vascular tissues. In this regard, we also confirmed that Ang II producing chymase is high in lung arteries of drug-induced pulmonary hypertensive rats (33).…”

Section: Chymase-dependent Tissue Ang II and Related Pathologysupporting

confidence: 79%

Tissue Angiotensin II Generating System by Angiotensin-Converting Enzyme and Chymase

2006

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Abstract. It had been believed that angiotensin II (Ang II) was produced by the reninangiotensin system (RAS), which was established in the 1950's. After a while, people realized that the multiple functions of Ang II could not be explained by the conventional RAS. We have tried to determine the existence of the tissue Ang II generating system. At first, we found that vascular angiotensin-converting enzyme (ACE) was increased to generate local Ang II in the vessels of hypertension and was enhanced in lipid-loaded atherosclerosis, to respond to ACE inhibitor or Ang II antagonist (ARB). In both cases, Ang II production in vessels was independent from the systemic RAS that was estimated by the plasma renin activity. On the way to clarifying the roles of the vascular ACE, we noticed that vascular Ang II production was not completely suppressed by ACE inhibitor alone. This evidence led us to discover different types of chymase as a new Ang II producing enzyme. Now, we have obtained a strategy to distinguish the Ang II one by one, that is, circulating RAS derived, tissue ACE derived, and chymase derived. It is essential to understand not only the intracellular mechanisms of Ang II but also the process of Ang II productions in each disease to show accurate indications of the effectiveness of ACE inhibitor, ARB, and chymase inhibitor.

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“…The involvement of mast cells in the development of PAH has received little attention, although they may be of specific interest since mast cells are known as potent angiogenic stimulators (8,24). Mast cells may play a role in angiotensin II-mediated vasoconstriction (18), supposedly via specific serine proteases from their granules (14,21). Chymase, one of the serine proteases excreted by mast cells, is involved in the conversion of angiotensin I to angiotensin II (18) and of big endothelin to endothelin-1 (9), two powerful vasoconstrictors with mitogenic properties.…”

Section: Discussionmentioning

confidence: 99%

“…Mast cells may play a role in angiotensin II-mediated vasoconstriction (18), supposedly via specific serine proteases from their granules (14,21). Chymase, one of the serine proteases excreted by mast cells, is involved in the conversion of angiotensin I to angiotensin II (18) and of big endothelin to endothelin-1 (9), two powerful vasoconstrictors with mitogenic properties. Together, these data suggest that the presence of excessive mast cells in pulmonary arteries of human and experimental PAH contributes to the development of the disease.…”

Section: Discussionmentioning

confidence: 99%

Gene expression profile in flow-associated pulmonary arterial hypertension with neointimal lesions

Albada

Bartelds

Wijnberg

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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expression profile in flow-associated pulmonary arterial hypertension with neointimal lesions. Am J Physiol Lung Cell Mol Physiol 298: L483-L491, 2010. First published December 18, 2009 doi:10.1152/ajplung.00106.2009.-Pulmonary arterial hypertension (PAH) is a pulmonary angioproliferative disease with high morbidity and mortality, characterized by a typical pattern of pulmonary vascular remodeling including neointimal lesions. In congenital heart disease, increased pulmonary blood flow has appeared to be a key mediator in the development of these characteristic lesions, but the molecular mechanisms underlying the pulmonary vascular lesions are largely unknown. We employed a rat model of flow-associated PAH, which induced specific pulmonary neointimal lesions. We identified gene expression profiles in rats specifically related to the addition of increased pulmonary blood flow to monocrotaline and the associated occurrence of neointimal lesions. Increased pulmonary blood flow induced the expression of the transcription factors activating transcription factor-3 (ATF3) and early growth response factor-1 (EGR-1), for which presence was confirmed in neointimal lesions. Monocrotaline alone induced increased numbers of activated mast cells and their products. We further identified molecular pathways that may be involved in treatment with the prostacyclin analog iloprost, a vasoactive compound with clinically beneficial effects in patients with PAH, which were similar to pathways described in samples from patient studies. These pathways, associated with the development of angioproliferative lesions as well as with the response to therapy in PAH, may provide new therapeutic targets.remodeling; congenital heart defects PULMONARY ARTERIAL HYPERTENSION (PAH) is a progressive angioproliferative disease with high morbidity and mortality (4), associated with a characteristic pattern of vascular remodeling of the small pulmonary arteries. This vascular remodeling consists of proliferation of endothelial and smooth muscle cells, fibrosis, and inflammation, leading to formation of concentric neointimal lesions and plexiform lesions (37). These latter vascular lesions can be regarded as pathognomonic for PAH (37). Although the histopathology is well-described, the pathogenesis of the disease and its typical vascular lesions is largely unknown (28). In patients with congenital heart diseases that develop PAH, increased pulmonary blood flow has been clinically identified as a key mediator in the development of the pathognomonic vascular lesions of PAH (10, 33, 37) and through unknown mechanisms.Prostacyclin, a vascular endothelium-derived vasoactive compound with vasodilatory and antiproliferative properties, is believed to interfere with the pathogenesis, since prostacyclin analogs have been demonstrated to have beneficial clinical effects in patients with PAH (3, 30). These analogs have been suggested to be able to reverse the pulmonary vascular remodeling process of pulmonary hypertension (PH) in experimental settings (31), altho...

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Role of Chymase-Dependent Angiotensin II Formation in Monocrotaline-Induced Pulmonary Hypertensive Rats

Cited by 19 publications

References 28 publications

Effects of Telmisartan on Right Ventricular Remodeling Induced by Monocrotaline in Rats

Effects of Telmisartan on Right Ventricular Remodeling Induced by Monocrotaline in Rats

Tissue Angiotensin II Generating System by Angiotensin-Converting Enzyme and Chymase

Gene expression profile in flow-associated pulmonary arterial hypertension with neointimal lesions

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