Inhibition of angiotensin‐converting enzyme protects endothelial cell against hypoxia/reoxygenation injury

Fujita, Noriko; Manabe, Hiroki; Yoshida, Norimasa; Matsumoto, Naohito; Ochiai, Jun; Masui, Yasuharu; Uemura, Manabu; Naito, Yuji; Yoshikawa, Toshikazu

doi:10.1002/biof.5520110404

Cited by 16 publications

(13 citation statements)

References 23 publications

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“…However, a number of other ACE-inhibitors have also been shown to inhibit apoptosis in other tissues, including enalapril (32), quinaprilat (36), and captopril (35), as well as other inhibitors of components of the ACE/Angiotensin signaling cascade, such as angiotensin receptor blockers (30,40).…”

Section: Discussionmentioning

confidence: 99%

“…Studies using pharmacologic ACE inhibition (ACE-I) have shown that ACE-I significantly reduces apoptosis in pulmonary and cardiac cells (31)(32)(33)(34); and this reduction of apoptosis exhibits a concentration dependent effect (34). In addition, investigators have shown that Ang II is required for the induction of apoptosis in alveolar epithelial cells and cardiac myocytes (31)(32)(33)(34)(35)(36). The production of Ang II is precisely what ACE-I prevents.…”

Section: Introductionmentioning

confidence: 99%

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Reduced Severity of a Mouse Colitis Model with Angiotensin Converting Enzyme Inhibition

et al. 2007

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Ulcerative colitis is characterized by elevated rates of epithelial cell apoptosis, and an up-regulation of pro-apoptotic cytokines including tumor necrosis factor alpha (TNF-α). Recently, angiotensin converting enzyme (ACE) has been shown to promote apoptosis. In addition, pharmacologic ACE inhibition (ACE-I) both prevents apoptosis and reduces TNF-α expression in vitro. We hypothesized that ACE-I, using enalaprilat, would decrease colonic epithelial cell apoptosis and reduce colitis severity in the dextran sulfate sodium (DSS)-induced colitis model in mice. We assessed the severity of colitis, and colonic epithelial cell apoptosis, after administration of DSS. Mice were given either daily ACE-I treatment or daily placebo. ACE-I treatment markedly improved clinical outcomes. In addition, ACE-I treatment significantly reduced the maximum histopathologic colitis grade. ACE-I also dramatically reduced the epithelial apoptotic rate. To investigate the mechanism by which ACE-I reduced apoptosis; we measured TNF-α, Bcl-2, and Bax expression. TNF-α mRNA was significantly lower with ACE-I treatment compared to placebo at every time point; as was the ratio of Bax to Bcl-2. We conclude that ACE-I reduces the severity of DSS-induced colitis and reduces epithelial cell apoptosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Reduced Severity of a Mouse Colitis Model with Angiotensin Converting Enzyme Inhibition

et al. 2007

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“…Nearly all of the in vitro functional studies that have demonstrated real EC protection against noxious stimuli by BK, either added or endogenously produced via ACEi and ARA treatments, were conducted on macrovascular ECs from conductance vessels such as the bovine aorta (Gryglewski et al, 2001), the human umbilical vein (HUVEC) (Kono et al, 2002;Ceconi et al, 2007), and the human aorta (HAEC) (Fujita et al, 2000). There is no doubt about functional phenotypic heterogeneity of ECs between macro-and microvessels.…”

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confidence: 98%

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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“…59 ACE inhibitors also improve EC survival after hypoxic injury via B 2 R-NO-dependent pathways. 60 In addition, these drugs induce B 1 R in the renal vasculature and increase NO production from EC expressing these receptors. 61 Recently, a novel mechanism for ACE inhibitors has been discovered that involves signal transduction by ACE itself (Figure 4).…”

Section: Ace Inhibitorsmentioning

confidence: 99%

Angiotensin II and the Endothelium

2005

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Abstract-The initial view of the renin-angiotensin system focused on the role of angiotensin II as a hormone involved in blood pressure control, based on its role in renal salt and water regulation, as well as central nervous system (thirst) and vascular smooth muscle tone. Subsequent data showed a role for angiotensin II in long-term effects on cardiovascular structure, including cardiac hypertrophy and vascular remodeling. I n this review, we discuss the evolving role of angiotensin II (Ang II) as a regulator of endothelial cell (EC) function. In particular, recent clinical trials of angiotensin-converting enzyme (ACE) inhibitors and Ang II receptor blockers (ARBs) suggest that several of the beneficial effects of these drugs are mediated by inhibiting Ang II effects at the endothelium. Initially, Ang II was identified as a hormone that controlled blood pressure based on regulation of renal salt and water metabolism, central nervous system mechanisms (thirst and sympathetic outflow), and vascular smooth muscle cell (VSMC) tone. 1 Later, Ang II was found to exert long-term effects on tissue structure, including cardiac hypertrophy, vascular remodeling, and renal fibrosis. Importantly, recent human studies with ACE inhibitors and ARBs have yielded exciting clinical benefits such as decreased incidence of stroke, diabetes mellitus, and end-stage renal disease. 2,3 This article discusses the endothelium-specific effects of these drugs and Ang II, based on the concept of diverse signals and effects mediated by multiple angiotensin receptors (AT 1 R, AT 2 R, and AT 4 R), multiple angiotensin I-and Ang II-derived peptides [Ang III, Ang IV, and Ang (1-7)], and vascular bed-specific events (Figure 1). The enzymes that control generation of these peptides, including ACE, ACE2, endopeptidases, and aminopeptidases, interact with each other. In addition, drugs such as ACE inhibitors and ARBs that inhibit formation of Ang II and binding to its receptor also modify the expression of receptors for Ang II and of other vasoactive hormones, including bradykinin and adrenomedullin. This complex interplay of pathways helps to explain the findings that Ang II can have both beneficial and detrimental effects on vascular function. Effects of Angiotensin Type-1 ReceptorThe AT 1 R has been shown to mediate most of the physiological actions of Ang II. However, as discussed, important regulatory roles for the AT 2 R and AT 4 R, have been defined, especially in EC. Recent data show several pathways by which the AT 1 R and AT 2 R modulate EC function. 4 ApoptosisAng II has been shown both to increase and decrease EC apoptosis, suggesting that other factors influence the actions of Ang II (eg, presence of oxidized low-density lipoprotein [oxLDL]). In fact, both the AT 1 R and the AT 2 R have been suggested to mediate EC apoptosis. 5,6 As discussed further, we speculate that the relative AT 1 R and AT 2 R expression levels are important determinants of the effects of Ang II in EC (Figure 2). Ang II-mediated EC apoptosis is in part mediated b...

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Inhibition of angiotensin‐converting enzyme protects endothelial cell against hypoxia/reoxygenation injury

Cited by 16 publications

References 23 publications

Reduced Severity of a Mouse Colitis Model with Angiotensin Converting Enzyme Inhibition

Reduced Severity of a Mouse Colitis Model with Angiotensin Converting Enzyme Inhibition

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

Angiotensin II and the Endothelium

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