Effects of Bradykinin on Cardiovascular Remodeling in Renovascular Hypertensive Rats

Tanaka, Yasuyuki; Nagai, Makoto; Date, Taro; Okada, Takuya; Abe, Yuichi; Seki, Shuichi; Taniguchi, Masayuki; Taniguchi, Ikuo; Mochizuki, Seibu

doi:10.1291/hypres.27.865

Cited by 30 publications

(17 citation statements)

References 30 publications

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“…However, massive fibrosis of the RV wall, characteristic of right ventricular dysplasia, was not observed in NEPAS/HIF-3␣ Ϫ/Ϫ hearts. Furthermore, the expression of brain natriuretic peptide mRNA, known to be elevated in cardiomyopathy (32), was normal in the mutant RV (data not shown). Hence, the available lines of evidence do not support the contention that cardiomyopathy is the cause of RV enlargement in NEPAS/HIF-3␣ Ϫ/Ϫ mice.…”

Section: [N ϭ 8]) and Nepas/hif-3␣mentioning

confidence: 91%

Abnormal Heart Development and Lung Remodeling in Mice Lacking the Hypoxia-Inducible Factor-Related Basic Helix-Loop-Helix PAS Protein NEPAS

Yamashita¹,

Onodera²,

Nagano³

et al. 2008

Molecular and Cellular Biology

147

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Hypoxia-inducible factors (HIFs) are crucial for oxygen homeostasis during both embryonic development and postnatal life. Here we show that a novel HIF family basic helix-loop-helix (bHLH) PAS (Per-Arnt-Sim) protein, which is expressed predominantly during embryonic and neonatal stages and thereby designated NEPAS (neonatal and embryonic PAS), acts as a negative regulator of HIF-mediated gene expression. NEPAS mRNA is derived from the HIF-3␣ gene by alternative splicing, replacing the first exon of HIF-3␣ with that of inhibitory PAS. NEPAS can dimerize with Arnt and exhibits only low levels of transcriptional activity, similar to that of HIF-3␣. NEPAS suppressed reporter gene expression driven by HIF-1␣ and HIF-2␣. By generating mice with a targeted disruption of the NEPAS/HIF-3␣ locus, we found that homozygous mutant mice (NEPAS/ HIF-3␣ ؊/؊ ) were viable but displayed enlargement of the right ventricle and impaired lung remodeling. The expression of endothelin 1 and platelet-derived growth factor ␤ was increased in the lung endothelial cells of NEPAS/HIF-3␣-null mice. These results demonstrate a novel regulatory mechanism in which the activities of HIF-1␣ and HIF-2␣ are negatively regulated by NEPAS in endothelial cells, which is pertinent to lung and heart development during the embryonic and neonatal stages.Hypoxia-inducible factors (HIFs) are crucial for oxygen homeostasis during both embryonic development and postnatal life. HIFs are heterodimeric transcription factors consisting of ␣ and ␤ subunits. To date, three ␣ subunits (HIF-1␣, HIF-2␣, and HIF-3␣) and one ␤ subunit (HIF-1␤, also called Arnt [aryl hydrocarbon receptor nuclear translocator]) have been identified (10, 34, 37). Oxygen-dependent activity of HIFs is mainly regulated through the stability of their ␣ subunits. Under the normoxic condition, HIF-␣ protein is rapidly degraded through the ubiquitin-proteasomal pathway. During this process, HIF-␣ is hydroxylated by proline hydroxylases and specifically interacts with the von Hippel-Lindau (VHL) tumor suppressor protein (8, 21), which acts as a component of E3 ubiquitin ligase and targets HIF-␣ molecules for ubiquitination and subsequent degradation (12). Under low oxygen tension, hydroxylation of HIF-␣ is significantly reduced because the activity of proline hydroxylases is repressed by hypoxia. Since VHL can recognize exclusively the hydroxylated HIF-␣ molecules, in the hypoxic condition HIF-␣ is stabilized and activates transcription of target genes with Arnt in the nucleus.Although it is indisputable that this ubiquitin-proteasomal pathway plays a central role in determining HIF activity, an additional regulatory mechanism should be considered under certain conditions. For instance, the availability of oxygen is limited in utero and embryos are continuously exposed to hypoxia (17). Under such conditions, it is likely that HIF-␣ proteins are no longer degraded and accumulate into the nucleus. Given the fact that both HIF-1␣ and HIF-2␣ are required for early embryonic development (13,25,33), HIF...

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Section: [N ϭ 8]) and Nepas/hif-3␣mentioning

confidence: 91%

Abnormal Heart Development and Lung Remodeling in Mice Lacking the Hypoxia-Inducible Factor-Related Basic Helix-Loop-Helix PAS Protein NEPAS

Yamashita¹,

Onodera²,

Nagano³

et al. 2008

Molecular and Cellular Biology

147

View full text Add to dashboard Cite

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“…In dogs, detailed analyses have revealed that the RAS existing in cardiac tissue has a crucial role in the development of hypertrophy [2]. Cardiac ACE plays a role not only in generating Ang II, which provokes cardiac hypertrophy and fibrosis through Ang II type 1 (AT1) receptor signaling [4,12,23], but also in increasing cardiac fibrosis by catalyzing the degradation of bradykinin into inactive metabolites [3,9,26,30]. Similarly, cardiac chymase plays a role not only in converting Ang I to Ang II [31], but also in promoting direct collagen production [28,29].…”

Section: Discussionmentioning

confidence: 99%

Cardiac Remodeling and Angiotensin II-Forming Enzyme Activity of the Left Ventricle in Hamsters with Chronic Pressure Overload Induced by Ascending Aortic Stenosis

Shimizu

Tanaka

Fukuyama

et al. 2006

The Journal of Veterinary Medical Science

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ABSTRACT. Cardiac remodeling and angiotensin II-forming enzyme activity of the left ventricle on chronic pressure overload were studied in male Syrian hamsters, whose chymase activity is similar to that of dogs. Pressure overload was achieved by banding at the ascending aorta (aortic stenosis). Echocardiography, histological analysis, and analysis of cardiac angiotensin-converting enzyme and chymase-like activities were performed. At 10 weeks after banding, concentric hypertrophy of the left ventricle was evident. At 20 weeks after banding, the ventricular weight-to-body ratio, cardiac fibrosis, and cardiac chymase-like activity were significantly increased, while cardiac angiotensin-converting enzyme activity was significantly decreased. This suggests that cardiac chymase, compared with cardiac angiotensin-converting enzyme, was activated against the chronic pressure overload and was responsible for the cardiac remodeling through the formation of angiotensin II. Considering the utility of the rodents, the interspecies similarity of the Ang II-forming pathway, and the effect of chymase in the hamsters, the present model is considered useful for studies evaluating the effect of Ang II and chymase in the canine heart with chronic pressure overload.

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“…The methods have been described in detail in 2 previous reports. 11,16) The main procedures used in the present study were as follows. RHT rats were produced by constricting the left renal artery with a silver clip (two-kidney one-clip: 2K1C) in male Wistar rats weighing 130 to 150 g. One week after the operation, rats with a systolic blood pressure (SBP) of over 140 mmHg were considered as representing the RHT model.…”

Section: Methodsmentioning

confidence: 99%

“…To estimate the degree of myocardial fibrosis, photomicrographic figures of the sections were digitized and the fibrotic areas were assigned numerical values using NIH image software. 16) Vascular tissue changes were evaluated according to the method described by Ito, et al…”

Section: Methodsmentioning

confidence: 99%

Combined Treatment With Valsartan and Spironolactone Prevents Cardiovascular Remodeling in Renovascular Hypertensive Rats

et al. 2006

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SUMMARYTreatment with an angiotensin blocker (ARB) and an aldosterone blocker has been shown to have beneficial effects on cardiac remodeling in several cardiac diseases. It is still not clear whether the combination of these drugs is more effective against cardiac remodeling than the use of either agent alone. We examined the effects of combined treatment with valsartan, an ARB, and spironolactone, an aldosterone blocker, on cardiac remodeling in the renovascular hypertensive (RHT) rat. The RHT rats were divided into 4 groups administered valsartan (3 mg/kg/day, ARB group), spironolactone (4 mg/kg/day, SPRL group), both drugs at these doses (combined group), or neither drug (untreated RHT group). After 5 weeks, systolic blood pressure was significantly reduced in the 3 treatment groups, however, there were no significant differences in the extent of blood pressure reduction among the 3 treatment groups. The heart weight/body weight ratio in each of the 3 treatment groups was significantly lower than that in the untreated RHT group. The degree of cardiac and perivascular fibrosis in the SPRL group and the combined group were significantly lower than that in the untreated RHT group. Myocyte remodeling in the ARB group and in the combined group was significantly smaller than that in the untreated RHT group. These results suggest that SPRL treatment prevents cardiac and perivascular fibrosis and ARB treatment suppresses the cellular hypertrophy of myocytes, and that, therefore, combined treatment with both drugs prevents cardiac remodeling by acting against both myocyte hypertrophy and cardiac fibrosis in RHT rats. (Int Heart J 2006; 47: 783-793)

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Effects of Bradykinin on Cardiovascular Remodeling in Renovascular Hypertensive Rats

Cited by 30 publications

References 30 publications

Abnormal Heart Development and Lung Remodeling in Mice Lacking the Hypoxia-Inducible Factor-Related Basic Helix-Loop-Helix PAS Protein NEPAS

Abnormal Heart Development and Lung Remodeling in Mice Lacking the Hypoxia-Inducible Factor-Related Basic Helix-Loop-Helix PAS Protein NEPAS

Cardiac Remodeling and Angiotensin II-Forming Enzyme Activity of the Left Ventricle in Hamsters with Chronic Pressure Overload Induced by Ascending Aortic Stenosis

Combined Treatment With Valsartan and Spironolactone Prevents Cardiovascular Remodeling in Renovascular Hypertensive Rats

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