Effects of Captopril and Telmisartan on Matrix Metalloproteinase-2 and -9 Expressions and Development of Left Ventricular Fibrosis Induced by Isoprenaline in Rats

Okada, Muneyoshi; Kosaka, Natsuko; Hoshino, Yoshikazu; Yamawaki, Hideyuki; Hara, Yukio

doi:10.1248/bpb.33.1517

Cited by 23 publications

(18 citation statements)

References 27 publications

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“…The RAS system increases expression of MMPs and modulates the balance between MMPs and tissue inhibitors of MMPs (TIMPs) in many heart and renal diseases (21)(22)(23)(24). Previous cancer studies have demonstrated that AngII augments the migration and invasion of choriocarcinoma cells through the AT1R and induces MMP-2 and MMP-9 expression in gastric cancer cells (25)(26)(27).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of ACE2 produces antitumor effects via inhibition of angiogenesis and tumor cell invasion in vivo and in vitro

Wan

2011

Oncol Rep

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Abstract. Angiotensin II (AngII) is a multifunctional bioactive peptide in the renin-angiotensin system (RAS). Angiotensinconverting enzyme 2 (ACE2) is a newly identified component of RAS. The role of AngII and ACE2 in the metastasis of non-small cell lung cancer (NSCLC) and the effects on matrix metalloproteinases (MMPs) are still unknown. In the present study, the anti-invasive effect and mechanism of ACE2 were investigated in vitro and in vivo. Results of a transwell assay showed that the overexpression of ACE2 reduces the invasive ability of A549 cells in vitro. According to the results of qRT-PCR and Western blot analysis, the inhibitory role of ACE2 was mediated through the down-regulation of MMP-2 and MMP-9. Additionally, we confirmed that the overexpression of ACE2 inhibited cell growth and VEGFa production while simultaneously suppressing ACE and angiotensin II type 1 receptor (AT1R) expression in human lung cancer xenografts. These results suggest that the overexpression of ACE2 may potentially suppress the invasion and angiogenesis of NSCLC.

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Section: Discussionmentioning

confidence: 99%

Overexpression of ACE2 produces antitumor effects via inhibition of angiogenesis and tumor cell invasion in vivo and in vitro

Wan

2011

Oncol Rep

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“…anesthesia as described previously [7,17]. Briefly, the catheter filled with a heparin-saline solution was inserted into carotid artery with a small incision.…”

Section: Methodsmentioning

confidence: 99%

A Novel Adipocytokine, Omentin, Inhibits Agonists-Induced Increases of Blood Pressure in Rats

Kazama

Okada

Hara

et al. 2013

The Journal of Veterinary Medical Science

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ABSTRACT. Omentin is a recently identified adipocytokine, and we previously demonstrated that omentin played anti-inflammatory roles in vascular endothelial and smooth muscle cells. We also demonstrated that omentin induced vasodilation in rat isolated blood vessels. However, effects of omentin on blood pressure (BP) Adipocytes can secrete a variety of cytokines, termed adipocytokine. Obesity with an accumulation of visceral fat is one of the main risk factors for cardiovascular diseases, including hypertension. Adipocytes enlarged by obesity may increase or decrease the production and secretion of adipocytokine. Adipocytokine is thought to regulate obesity-related hypertension by directly acting on vascular system [13,14].Omentin is a recently identified adipocytokine consisting of 313 amino acids [9]. Secretion and plasma concentration of omentin decrease in the obese patients, but increase after a weight loss [2]. We previously demonstrated that omentin was anti-inflammatory in cultured vascular endothelial and smooth muscle cells [5,16]. In addition, we demonstrated that omentin induced vasodilation in rat isolated blood vessels via stimulating endothelial nitric oxide (NO) production [15]. While it is presumed that omentin could regulate blood pressure (BP) in vivo, effects of omentin on BP remain to be determined. Here, we for the first time provided the evidence that omentin can regulate BP in rats. MATERIALS AND METHODS Materials:Reagent sources were as follows: recombinant omentin (BioVendor, Candler, NC, U.S.A.); noradrenaline (NA) and angiotensin II (Ang II) (Sigma-Aldrich, St. Louis, MO, U.S.A.); dimorpholamine (Eisai Co., Ltd., Tokyo, Japan); N G -nitro-l-arginine methyl ester (L-NAME) (Dojindo, Kumamoto, Japan).Physical parameters of rats: Physical parameters of normal Wistar rats (Clea Japan Inc., Tokyo, Japan) or L-NAME-treated Wistar rats (6-10-week-old) were measured. Body weight, heart rate (HR), systolic blood pressure (BP) (SBP), mean BP (MBP) and diastolic BP (DBP) represent the average value (Table 1). Noninvasive BP in conscious rats was measured using a tail-cuff method after heating the rats (38°C) (Softron, Tokyo, Japan) [6,11,12]. L-NAME was dissolved in drinking water and given to rats (80 mg/kg, 1 day).Direct BP measurement: BP and HR of male Wistar rats (130-350 g, 6-10-week-old) were measured under urethane (1.5 g/kg, i.p.) anesthesia as described previously [7,17]. Briefly, the catheter filled with a heparin-saline solution was inserted into carotid artery with a small incision. Catheter was connected to MLT0670 BP transducer (ADInstruments, Colorado Springs, CO, U.S.A.). SBP, MBP and DBP were measured and recorded using ML117 BP Amp (ADInstruments), ML825 PowerLab 2/25 (ADInstruments) system and Chart5 software (ADInstruments). HR was calculated by a cyclic measurement of BP recording. After omentin (0.06-1.8 µg/kg) or saline was intravenously applied for 5 min through the catheter inserted into saphenous vein, NA (0.02-2 µg/kg), Ang II (0.01-10 µg/kg) or dimorpholamine (3 mg/...

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“…Furthermore, captopril but not amlodipine was shown to reduce fibrotic markers in experimental nonalcoholic steatohepatitis (NASH)17 or after bile-duct ligation 15. However, captopril is also reported to directly interfere with matrix metalloproteinase activity, thus inhibiting the degradation of extracellular matrix and further favoring fibrotic tissue changes 13. On the other hand, captopril may induce upregulation of metallopeptidase with thrombospondin type 1 (ADAMTS-1), which is known to accelerate the degradation of type I collagen,34 which would compensate for the above.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to the aforementioned calcium channel blockers (calcium antagonists), these include diuretics, angiotensin-converting enzyme (ACE)-inhibitors, aldosterone antagonists, renin inhibitors, as well as adrenergic receptor agonists and antagonists (α- and β-blockers). There are hints that certain antihypertensives influence fibrosis in vivo, as reported for myocardial and renal fibrosis 12,13. There are reports that amlodipine and captopril may also be effective against lung and liver fibrosis as well as keloid formation 14–17.…”

Section: Introductionmentioning

confidence: 97%

“…There are reports that amlodipine and captopril may also be effective against lung and liver fibrosis as well as keloid formation 14–17. However, the available data are contradictory, eg, the ACE-inhibitor captopril may reduce as well as enhance left ventricular fibrosis in rats 12,13. As patients with ALD often suffer from high blood pressure, they rely on an antihypertensive treatment.…”

Section: Introductionmentioning

confidence: 99%

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The right choice of antihypertensives protects primary human hepatocytes from ethanol- and recombinant human TGF-β1-induced cellular damage

Ehnert¹,

Lukoschek

Bachmann

et al. 2013

HMER

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BackgroundPatients with alcoholic liver disease (ALD) often suffer from high blood pressure and rely on antihypertensive treatment. Certain antihypertensives may influence progression of chronic liver disease. Therefore, the aim of this study is to investigate the impact of the commonly used antihypertensives amlodipine, captopril, furosemide, metoprolol, propranolol, and spironolactone on alcohol-induced damage toward human hepatocytes (hHeps).MethodshHeps were isolated by collagenase perfusion. Reactive oxygen species (ROS) were measured by fluorescence-based assays. Cellular damage was determined by lactate-dehydrogenase (LDH)-leakage. Expression analysis was performed by reverse-transcription polymerase chain reaction and Western blot. Transforming growth factor (TGF)-β signaling was investigated by a Smad3/4-responsive luciferase-reporter assay.ResultsEthanol and TGF-β1 rapidly increased ROS in hHeps, causing a release of 40%–60% of total LDH after 72 hours. All antihypertensives dose dependently reduced ethanol-mediated oxidative stress and cellular damage. Similar results were observed for TGF-β1-dependent damage, except for furosemide, which had no effect. As a common mechanism, all antihypertensives increased heme-oxygenase-1 (HO-1) expression, and inhibition of HO-1 activity reversed the protective effect of the drugs. Interestingly, Smad3/4 signaling was reduced by all compounds except furosemide, which even enhanced this profibrotic signaling. This effect was mediated by expressional changes of Smad3 and/or Smad4.ConclusionsOur results suggest that antihypertensives may both positively and negatively influence chronic liver disease progression. Therefore, we propose that in future patients with ALD and high blood pressure, they could benefit from an adjusted antihypertensive therapy with additional antifibrotic effects.

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Effects of Captopril and Telmisartan on Matrix Metalloproteinase-2 and -9 Expressions and Development of Left Ventricular Fibrosis Induced by Isoprenaline in Rats

Cited by 23 publications

References 27 publications

Overexpression of ACE2 produces antitumor effects via inhibition of angiogenesis and tumor cell invasion in vivo and in vitro

Overexpression of ACE2 produces antitumor effects via inhibition of angiogenesis and tumor cell invasion in vivo and in vitro

A Novel Adipocytokine, Omentin, Inhibits Agonists-Induced Increases of Blood Pressure in Rats

The right choice of antihypertensives protects primary human hepatocytes from ethanol- and recombinant human TGF-β1-induced cellular damage

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Effects of Captopril and Telmisartan on Matrix Metalloproteinase-2 and -9 Expressions and Development of Left Ventricular Fibrosis Induced by Isoprenaline in Rats

Cited by 23 publications

References 27 publications

Overexpression of ACE2 produces antitumor effects via inhibition of angiogenesis and tumor cell invasion in vivo and in vitro

Overexpression of ACE2 produces antitumor effects via inhibition of angiogenesis and tumor cell invasion in vivo and in vitro

A Novel Adipocytokine, Omentin, Inhibits Agonists-Induced Increases of Blood Pressure in Rats

The right choice of antihypertensives protects primary human hepatocytes from ethanol- and recombinant human TGF-&beta;1-induced cellular damage

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The right choice of antihypertensives protects primary human hepatocytes from ethanol- and recombinant human TGF-β1-induced cellular damage