An AT1-Receptor Antagonist and an Angiotensin-Converting Enzyme Inhibitor Protect Against Hypoxia-Induced Apoptosis in Human Aortic Endothelial Cells Through Upregulation of Endothelial Cell Nitric Oxide Synthase Activity

Matsumoto, Naoyuki; Manabe, Hiroki; Ochiai, Jun; Fujita, Noriko; Takagi, Tomohisa; Uemura, Manabu; Naito, Yuji; Yoshida, Norimasa; Oka, Saori; Yoshikawa, Toshikazu

doi:10.1097/01.shk.0000070734.34700.80

Cited by 15 publications

(12 citation statements)

References 36 publications

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“…The contention from our study has been that BK-separate from its action on blood pressure reduction-also plays a role in ensuring the low incidence of EC mortality (either necrotic or apoptotic in origin) and subsequent microvascular degeneration observed in animal disease models and patients treated with ACEi and ARA, the most frequently prescribed antihypertensive drugs (Pellacani et al, 1994;Liu et al, 1997;Duncan et al, 2000;Matsumoto et al, 2003;Feihl et al, 2006;Battegay et al, 2007). In line with this assertion are the in vitro results of the recent PERTINENT study, a substudy of the EUROPA clinical study (Ceconi et al, 2007), which showed that HUVEC cells exposed to serum from patients with coronary artery disease (CAD) had a significantly higher rate of apoptosis than cells exposed to serum from patients who had received the ACEi perindopril and from control groups.…”

Section: Discussionmentioning

confidence: 95%

“…Vasculoprotective effects of ACEi seem to be mediated by mechanisms that are partly independent of their blood pressure lowering effects (Feihl et al, 2006;Battegay et al, 2007). Angiotensin II type 1 receptor (AT1) antagonists (ARA) may also mediate part of their beneficial pro-survival effects on ECs, possibly through increased BK formation (Matsumoto et al, 2003;Campbell et al, 2005;Battegay et al, 2007).…”

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confidence: 99%

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Bradykinin protects against brain microvascular endothelial cell death induced by pathophysiological stimuli

Bovenzi

Savard

Morin

et al. 2009

Journal Cellular Physiology

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The morphological and functional integrity of the microcirculation is compromised in many cardiovascular diseases such as hypertension, diabetes, stroke, and sepsis. Angiotensin converting enzyme inhibitors (ACEi), which are known to favor bradykinin (BK) bioactivity by reducing its metabolism, may have a positive impact on preventing the microvascular structural rarefaction that occurs in these diseases. Our study was designed to test the hypothesis that BK, via B2 receptors (B2R), protects the viability of the microvascular endothelium exposed to the necrotic and apoptotic cell death inducers H(2)O(2) and LPS independently of hemodynamics. Expression (RT-PCR and radioligand binding) and functional (calcium mobilization with fura-2AM, and p42/p44MAPK and Akt phosphorylation assays) experiments revealed the presence of functional B2R in pig cerebral microvascular endothelial cells (pCMVEC). In vitro results showed that the cytocidal effects of H(2)O(2) and LPS on pCMVEC were significantly decreased by a BK pretreatment (MTT and crystal violet tests, annexin-V staining/FACS analysis), which was countered by the B2R antagonist HOE 140. BK treatment coincided with enhanced expression of the cytoprotective proteins COX-2, Bcl-2, and (Cu/Zn)SOD. Ex vivo assays on rat brain explants showed that BK impeded (by approximately 40%) H(2)O(2)-induced microvascular degeneration (lectin-FITC staining). The present study proposes a novel role for BK in microvascular endothelial protection, which may be pertinent to the complex mechanism of action of ACEi explaining their long-term beneficial effects in maintaining vascular integrity.

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Section: Discussionmentioning

confidence: 95%

mentioning

confidence: 99%

Bradykinin protects against brain microvascular endothelial cell death induced by pathophysiological stimuli

Bovenzi

Savard

Morin

et al. 2009

Journal Cellular Physiology

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“…Both receptors are known to induce apoptosis in different cell types (Dimmeler et al, 1997;Bonnet et al, 2001;Haulica et al, 2005). Vice versa, ACE inhibition has been shown to decrease apoptosis in various tissues (Diez et al, 1997;Odaka and Mizuochi, 2000;Matsumoto et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of angiotensin‐converting enzyme stimulates fracture healing and periosteal callus formation – role of a local renin‐angiotensin system

Garcia

Schwenzer

Slotta

et al. 2010

British J Pharmacology

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Background and purpose:The renin-angiotensin system (RAS) regulates blood pressure and electrolyte homeostasis. In addition, 'local' tissue-specific RAS have been identified, regulating regeneration, cell growth, apoptosis, inflammation and angiogenesis. Although components of the RAS are expressed in osteoblasts and osteoclasts, a local RAS in bone has not yet been described and there is no information on whether the RAS is involved in fracture healing. Therefore, we studied the expression and function of the key RAS component, angiotensin-converting enzyme (ACE), during fracture healing. Experimental approach: In a murine femur fracture model, animals were treated with the ACE inhibitor perindopril or vehicle only. Fracture healing was analysed after 2, 5 and 10 weeks using X-ray, micro-CT, histomorphometry, immunohistochemistry, Western blotting and biomechanical testing. Key results: ACE was expressed in osteoblasts and hypertrophic chondrocytes in the periosteal callus during fracture healing, accompanied by expression of the angiotensin type-1 and type-2 receptors. Perindopril treatment reduced blood pressure and bone mineral density in unfractured femora. However, it improved periosteal callus formation, bone bridging of the fracture gap and torsional stiffness. ACE inhibition did not affect cell proliferation, but reduced apoptotic cell death. After 10 week treatment, a smaller callus diameter and bone volume after perindopril treatment indicated an advanced stage of bone remodelling. Conclusions: Our study provides evidence for a local RAS in bone that influenced the process of fracture healing. We show for the first time that inhibition of ACE is capable of accelerating bone healing and remodelling.

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“…Apart from insulin, glimepiride, a third generation sulfonylurea [15], pioglitazone, a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, and a member of the thiazolidinedione family (TZD) [16], and metformin, a biguanide, are used for treatment of type 2 diabetes [9]. Candesartan, an angiotensin II receptor antagonist, and rosuvastatin, a competitive inhibitor of the enzyme HMG-CoA reductase, are used for management of hypertension and hyperlipidemia, respectively [17,18]. In addition, we have also studied BLX-1002, a novel thiazolidinedione with no structural resemblance to other TZDs [19], which does not appear to affect PPARs.…”

Section: Introductionmentioning

confidence: 99%

Effects of some anti-diabetic and cardioprotective agents on proliferation and apoptosis of human coronary artery endothelial cells

Eriksson

Erdogdu

Nyström

et al. 2012

Cardiovasc Diabetol

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BackgroundThe leading cause of death for patients suffering from diabetes is macrovascular disease. Endothelial dysfunction is often observed in type 2 diabetic patients and it is considered to be an important early event in the pathogenesis of atherogenesis and cardiovascular disease. Many drugs are clinically applied to treat diabetic patients. However, little is known whether these agents directly interfere with endothelial cell proliferation and apoptosis. This study therefore aimed to investigate how anti-diabetic and cardioprotective agents affect human coronary artery endothelial cells (HCAECs).MethodsThe effect of anti-diabetic and cardioprotective agents on HCAEC viability, proliferation and apoptosis was studied. Viability was assessed using Trypan blue exclusion; proliferation in 5 mM and 11 mM of glucose was analyzed using [3H]thymidine incorporation. Lipoapoptosis of the cells was investigated by determining caspase-3 activity and the subsequent DNA fragmentation after incubation with the free fatty acid palmitate, mimicking diabetic lipotoxicity.ResultsOur data show that insulin, metformin, BLX-1002, and rosuvastatin improved HCAEC viability and they could also significantly increase cell proliferation in low glucose. The proliferative effect of insulin and BLX-1002 was also evident at 11 mM of glucose. In addition, insulin, metformin, BLX-1002, pioglitazone, and candesartan significantly decreased the caspase-3 activity and the subsequent DNA fragmentation evoked by palmitate, suggesting a protective effect of the drugs against lipoapoptosis.ConclusionOur results suggest that the anti-diabetic and cardioprotective agents mentioned above have direct and beneficial effects on endothelial cell viability, regeneration and apoptosis. This may add yet another valuable property to their therapeutic effect, increasing their clinical utility in type 2 diabetic patients in whom endothelial dysfunction is a prominent feature that adversely affect their survival.

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An AT1-Receptor Antagonist and an Angiotensin-Converting Enzyme Inhibitor Protect Against Hypoxia-Induced Apoptosis in Human Aortic Endothelial Cells Through Upregulation of Endothelial Cell Nitric Oxide Synthase Activity

Cited by 15 publications

References 36 publications

Bradykinin protects against brain microvascular endothelial cell death induced by pathophysiological stimuli

Bradykinin protects against brain microvascular endothelial cell death induced by pathophysiological stimuli

Inhibition of angiotensin‐converting enzyme stimulates fracture healing and periosteal callus formation – role of a local renin‐angiotensin system

Effects of some anti-diabetic and cardioprotective agents on proliferation and apoptosis of human coronary artery endothelial cells

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