Abstract 097: Vascular Aging in Aldosterone Associated Hypertension: Role of NADPH Oxidase 1

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Adam Harvey ◽  
Augusto C Montezano ◽  
Katie Y Hood ◽  
Rheure A Lopes ◽  
Delyth Graham ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Mrna Levels ◽  
Vascular Aging ◽  
Spontaneously Hypertensive ◽  
Wky Rats ◽  
Vascular Phenotype ◽  
Gene Level ◽  
Nadph Oxidase 1 ◽  
Cell Cycle Inhibitors

The vascular phenotype in hypertension is characterised by features typically observed in the ageing vasculature. Pathophysiological processes underlying premature vascular aging in hypertension remains unclear but aldosterone (aldo) and oxidative stress may be important. We postulated that physiological aging is amplified in hypertension due to increased aldo-induced Nox activation and redox signalling. We used arteries from adult WKY (18 weeks), aged WKY (52 weeks) and adult stroke-prone spontaneously hypertensive (SHRSP) rats. Blood pressure was measured by tail-cuff. Vascular function/structure was analysed by myography. Gene level was assessed by qPCR and protein by immunoblotting. BP was increased in SHRSP (180.7±2.5 vs. 127±2.7 mmHg, p<0.05). Endothelial dysfunction was observed in vessels from SHRSP. Increased vascular contraction in aged WKY rats was similar to SHRSP rats (p<0.05 vs WKY). Increased vascular stiffness was observed in arteries from aged WKY and SHRSP compared to WKY rats. Nox2 (0.82±0.4/2.4±0.9 vs 0.22±0.2), NoxA1 (4.9±2/9.5±5 vs 1±0.3) and NoxO1 (1.9±0.6/4.1±1 vs 1±0.4) mRNA was increased (p<0.05; SHRSP/aged WKY vs WKY). Nox1 mRNA (2.3±0.8 vs 1.1±0.4) was only increased in SHRSP rats (p<0.05; vs WKY). Similarly, mRNA levels of MCP-1 (2.3±0.5/3.9±1.9 vs 0.3±0.1) and RANTES (7.4±2/6.3±1.7 vs 1.1±0.2), aging-related inflammatory markers, and cell cycle inhibitors, p21 (3.2±1.1/3.1±0.7 vs 1±0.1) and p27 (2.2±0.7/2±0.8 vs 0.4±0.1), were increased in SHRSP and aged WKY rats (p<0.05; SHRSP/aged WKY vs WKY). ROS production (VSMC: 1.74±0.4 AU/protein), H2AX (DNA damage; 1.3±0.1) and aldosterone (plasma; 99.5±19 pg/mL) levels were increased in SHRSP rats (p<0.05; vs WKY). Aldo-induced Nox1 mRNA expression and p66SHC activation was exacerbated in VSMCs from SHRSP rats; an effect blocked by ML171 (a Nox1 inhibitor) and blunted in VSMCs from Nox1 KO mice. In conclusion, endothelial dysfunction and vascular remodelling in hypertension are associated with increased aldo-mediated activation of pro-inflammatory and redox-sensitive pathways. These processes involve Nox1. Our findings identify an important role for aldo/Nox1/ROS in molecular processes underlying vascular changes of ageing in hypertension.

Abstract 13: Cholic Acid Supplementation Attenuates Hypertension In Spontaneously Hypertensive Stroke Prone Rats

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Bojun Zhang ◽  
Sriram Ayyaswamy ◽  
Robert M Bryan ◽  
David J Durgan
Keyword(s):  
Cholic Acid ◽  
Vascular Function ◽  
Vascular Endothelial ◽  
Spontaneously Hypertensive ◽  
Gut Dysbiosis ◽  
Wky Rats ◽  
Hyocholic Acid ◽  
Control Plasma ◽  
Number Of Bacteria

Recent studies have demonstrated a causal role of gut dysbiosis in the development of hypertension in several animal models. However, our understanding of the mechanisms linking gut dysbiosis to blood pressure (BP) regulation of the host is still lacking. One key mechanism by which the microbiota influences the host is through the generation/modification of metabolites, such as bile acids (BAs). BA signaling has been shown to influence many pathways involved in BP regulation, including systemic inflammation and vascular function. We previously observed that spontaneously hypertensive stroke prone rat (SHRSP) exhibited dysbiotic cecal microbiome, which included a significant increase in the genus Lactobacillus , known to sequester BAs within its cytosol and reduce BAs availability, when compared to WKY. Thus, we hypothesized that gut dysbiosis contributes to the development of hypertension by reducing bile acid signaling. We observed a significant reduction in 9 of 18 plasma BAs in SHRSPs, as compared to WKY. This included a 72% reduction in cholic acid (CA), a primary BA (n=7-8, p<0.05). We next examined the effects of CA supplementation (0.5% CA diet for 16 weeks) on systolic BP (SBP) in WKY and SHRSP. Within the 9 BAs that were reduced in SHRSP, CA and hyocholic acid were restored by CA treatment in SHRSP plasma to similar levels of that observed in WKY control plasma. Furthermore, CA treatment decreased SBP by 18 ±7mmHg at 20 weeks in SHRSP (n=7-8, p<0.05), but had no effect on SBP in WKY rats. Acetylcholine-induced vasodilation of the aorta was significantly impaired in SHRSP control by 40% (10 -6 μM ACh, 59.5% vs. 99.3%) as compared to WKY control (n=3-4, p<0.01). CA treatment significantly improved endothelium-dependent vasodilation in the aorta of SHRSP rats similar to that in WKY rats (n=3-4, p<0.05). CA treatment also altered a number of bacteria in the gut including restoration of relative abundance of Lactobacillus in SHRSP to the level of WKY controls. We conclude that reduced BA signaling contributes to the development of hypertension in SHRSP, and that CA treatment may be a potential therapeutic approach to attenuate vascular endothelial dysfunction and associated hypertension.

scholarly journals Reconstitution of autophagy ameliorates vascular function and arterial stiffening in spontaneously hypertensive rats

2019 ◽  
Vol 317 (5) ◽  
pp. H1013-H1027 ◽  
Author(s):  
Cameron G. McCarthy ◽  
Camilla F. Wenceslau ◽  
Fabiano B. Calmasini ◽  
Nicole S. Klee ◽  
Michael W. Brands ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Vascular Function ◽  
Spontaneously Hypertensive Rats ◽  
Cellular Aging ◽  
Experimental Hypertension ◽  
Dependent Manner ◽  
Vascular Aging ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Autophagic Activity

Insufficient autophagy has been proposed as a mechanism of cellular aging, as this leads to the accumulation of dysfunctional macromolecules and organelles. Premature vascular aging occurs in hypertension. In fact, many factors that contribute to the deterioration of vascular function as we age are accelerated in clinical and experimental hypertension. Previously, we have reported decreased autophagy in arteries from spontaneously hypertensive rats (SHRs); however, the effects of restoring autophagic activity on blood pressure and vascular function are currently unknown. We hypothesized that reconstitution of arterial autophagy in SHRs would decrease blood pressure and improve endothelium-dependent relaxation. We treated 14- to 18-wk-old Wistar rats ( n = 7 vehicle and n = 8 trehalose) and SHRs ( n = 7/group) with autophagy activator trehalose (2% in drinking water) for 28 days. Blood pressure was measured by radiotelemetry, and vascular function and structure were measured in isolated mesenteric resistance arteries (MRAs) using wire and pressure myographs, respectively. Treatment with trehalose had no effect on blood pressure in SHRs; however, isolated MRAs presented enhanced relaxation to acetylcholine, in a cyclooxygenase- and reactive oxygen species-dependent manner. Similarly, trehalose treatment shifted the relaxation to the Rho kinase (ROCK) inhibitor Y-27632 to the right, indicating reduced ROCK activity. Finally, trehalose treatment decreased arterial stiffness as indicated by the slope of the stress-strain curve. Overall these data indicate that reconstitution of arterial autophagy in SHRs improves endothelial and vascular smooth muscle function, which could synergize to prevent stiffening. As a result, restoration of autophagic activity could be a novel therapeutic for premature vascular aging in hypertension. NEW & NOTEWORTHY This work supports the concept that diminished arterial autophagy contributes to premature vascular aging in hypertension and that therapeutic reconstitution of autophagic activity can ameliorate this phenotype. As vascular age is a new clinically used index for cardiovascular risk, understanding this mechanism may assist in the development of new drugs to prevent premature vascular aging in hypertension. Listen to this article’s corresponding podcast at https://ajpheart.podbean.com/e/behind-the-bench-episode-one-cam-squared/ .

Tetrahydroxystilbene Glucoside Inhibits Excessive Autophagy and Improves Microvascular Endothelial Dysfunction in Prehypertensive Spontaneously Hypertensive Rats

2016 ◽  
Vol 44 (07) ◽  
pp. 1393-1412 ◽  
Author(s):  
Qianqian Dong ◽  
Wenjuan Xing ◽  
Feng Fu ◽  
Zhenghua Liu ◽  
Jie Wang ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Mesenteric Artery ◽  
Spontaneously Hypertensive Rats ◽  
Vascular Endothelial ◽  
Vascular Endothelial Function ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Tetrahydroxystilbene Glucoside

Autophagy exists in vascular endothelial cells, but the relationship between autophagy and blood vessel dysfunction in hypertension remains elusive. This study aimed to investigate role of autophagy in vascular endothelial dysfunction in prehypertension and hypertension and the underlying mechanisms involved. Furthermore, we sought to determine if and how tetrahydroxystilbene glucoside (TSG), a resveratrol analogue and active ingredient of Polygonum multiflorum Thunb used for its cardiovascular protective properties in traditional Chinese medicine, influences vascular endothelial function. Male spontaneously hypertensive rats (SHRs) aged 4 weeks (young) and 12 weeks (adult) were studied and the vascular function of isolated aorta and mesenteric artery was assessed in vitro. Compared with Wistar Kyoto rats (WKY), young and adult SHRs showed endothelial dysfunction of the aorta and mesenteric artery, along with decreased pAkt, pmTOR, and autophagic marker protein p62 and increased LC3 II/I in microvascular but not aortic tissues. TSG administration for 14 days significantly improved mesenteric vascular endothelial function, increased levels of pAkt and pmTOR, and decreased autophagy. Pretreatment of young SHRs with the mTOR inhibitor rapamycin blocked the antiautophagic and vasodilative effects of TSG. Moreover, TSG significantly activated Akt-mTOR signaling in HUVECs and reduced the autophagic levels in vitro, which were almost completely blocked by rapamycin. In summary, mesenteric endothelial dysfunction in prehypertensive SHRs was at least partly attributable to excessive autophagy in vascular tissues. TSG partly restored microvascular endothelial dysfunction through activating the Akt/mTOR pathway, which consequently suppressed autophagy, indicating that TSG could be potentially applied to protect vascular function against subclinical changes in prehypertension.

Endothelial dysfunction in Type 2 diabetes correlates with deregulated expression of the tail-anchored membrane protein SLMAP

2005 ◽  
Vol 289 (1) ◽  
pp. H206-H211 ◽  
Author(s):  
Hong Ding ◽  
Andrew G. Howarth ◽  
Malarvannan Pannirselvam ◽  
Todd J. Anderson ◽  
David L. Severson ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Microvascular Disease ◽  
Mesenteric Arteries ◽  
Mrna Levels ◽  
Important Indicator ◽  
Membrane Function

The Type 2 diabetic db/ db mouse experiences vascular dysfunction typified by changes in the contraction and relaxation profiles of small mesenteric arteries (SMAs). Contractions of SMAs from the db/ db mouse to the α1-adrenoceptor agonist phenylephrine (PE) were significantly enhanced, and acetylcholine (ACh)-induced relaxations were significantly depressed. Drug treatment of db/ db mice with a nonthiazolidinedione peroxisome prolifetor-activated receptor-γ agonist and insulin sensitizing agent 2-[2-(4-phenoxy-2-propylphenoxy)ethyl]indole-5-acetic acid (COOH) completely prevented the changes in endothelium-dependent relaxation, but, with the discontinuation of therapy, endothelial dysfunction returned. Dysfunctional SMAs were found to specifically upregulate the expression of a 35-kDa isoform of sarcolemmal membrane-associated protein (SLMAP), which is a component of the excitation-contraction coupling apparatus and implicated in the regulation of membrane function in muscle cells. Real-time PCR revealed high SLMAP mRNA levels in the db/ db microvasculature, which were markedly downregulated during COOH treatment but elevated again when drug therapy was discontinued. These data reveal that the microvasculature in db/ db mice undergoes significant changes in vascular function with the endothelial component of vascular dysfunction specifically correlating with the overexpression of SLMAP. Thus changes in SLMAP expression may be an important indicator for microvascular disease associated with Type 2 diabetes.

Expression of adrenomedullin 2/intermedin, a possible reno-protective peptide, is decreased in the kidneys of rats with hypertension or renal failure

2010 ◽  
Vol 299 (1) ◽  
pp. F128-F134 ◽  
Author(s):  
Takuo Hirose ◽  
Kazuhito Totsune ◽  
Nobuyoshi Mori ◽  
Takefumi Mori ◽  
Ryo Morimoto ◽  
...  
Keyword(s):  
Renal Impairment ◽  
Renal Tubules ◽  
Mrna Levels ◽  
Protective Effects ◽  
Spontaneously Hypertensive ◽  
Chronic Renal Impairment ◽  
Wky Rats ◽  
Potent Vasodilator ◽  
Wistar Kyoto ◽  
Receptor Activity Modifying Proteins

Adrenomedullin 2/intermedin (AM2/IMD) is a potent vasodilator peptide with organ-protective effects and is abundantly expressed in the kidney. We examined the expression of AM2/IMD in the kidneys of rats with hypertension or chronic renal impairment using quantitative RT-PCR, radioimmunoassay, and immunohistochemistry. Kidneys of 8-wk-old male spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were dissected into inner medulla, outer medulla, cortex, and glomerulus fractions. A rat renal impairment model was prepared by 5/6 nephrectomy in WKY rats. AM2/IMD mRNA levels were the highest in the cortex among four renal portions, and significantly lower in SHR than WKY rats in all renal portions. In the remnant kidneys of 5/6 nephrectomized rats, AM2/IMD mRNA levels were significantly decreased on days 3 and 56, whereas mRNA levels of calcitonin receptor-like receptor, receptor activity-modifying proteins-1 and -2, which form receptor for AM and AM2/IMD, were increased, compared with that in sham-operated rats. AM mRNA levels were decreased on day 3, but increased on day 56, after nephrectomy. Decreased immunoreactive AM2/IMD levels in the remnant kidneys of 5/6 nephrectomized rats on day 56 were confirmed by radioimmunoassay. The renal tubules were immunostained with anti-AM2/IMD antibody, with a decreased AM2/IMD immunostaining found in proximal tubular cells of 5/6 nephrectomized rats compared with sham-operated rats. In conclusion, intrarenal AM2/IMD expression is decreased in SHR and 5/6 nephrectomized rats. Given the organ-protective effects of AM2/IMD, the downregulation of AM2/IMD as an endogenous regulatory peptide may have a role in the progression of renal impairment.

Kinin B1 and B2 receptor mRNA expression in the hypothalamus of spontaneously hypertensive rats

2002 ◽  
Vol 80 (4) ◽  
pp. 258-263 ◽  
Author(s):  
F Qadri ◽  
W Häuser ◽  
O Jöhren ◽  
P Dominiak
Keyword(s):  
Mrna Expression ◽  
Spontaneously Hypertensive Rats ◽  
Mrna Levels ◽  
Hypertensive Rats ◽  
Kinin System ◽  
Spontaneously Hypertensive ◽  
Receptor Mrna ◽  
Wky Rats ◽  
Wistar Kyoto ◽  
Kallikrein Kinin System

The central hypertensive effects induced by bradykinin are known to be mediated via B2 receptors, which are present constitutively in the brain. B1 receptors are rapidly upregulated during inflammation, hyperalgesia, and experimental diabetes. The hypothalamus plays an important role in the regulation of cardiovascular homeostasis, and all components of kallikrein–kinin system have been identified in this area. Therefore, we analyzed the mRNA expression of B1 and B2 receptors in the hypothalamus of spontaneously hypertensive rats (SHR) by RT-PCR. Male SHR were studied at three different ages corresponding to the three phases in the development of hypertension: (i) 3–4 (prehypertensive), (ii) 7–8 (onset of hypertension), and (iii) 12–13 weeks (established hypertension) after birth, and compared with age-matched Wistar–Kyoto (WKY) rats. At all ages tested, B2 receptor mRNA levels in the hypothalamus of SHR were higher than age-matched WKY rats (p < 0.001). However, the B1 receptor mRNA levels were higher at the established phase of hypertension only. We conclude that B1 and B2 receptor mRNA are differentially expressed in the hypothalamus of SHR and may play different roles in the pathogenesis of hypertension: upregulation of B2 receptor mRNA from early age may participate in the pathogenesis of hypertension, whereas an upregulation of B1 receptor mRNA in the established phase of hypertension may reflect an epiphenomenon in essential hypertension.Key words: kinin receptors, mRNA expression, hypothalamus, SHR, WKY.

Insulin resistance in spontaneously hypertensive rats is associated with endothelial dysfunction characterized by imbalance between NO and ET-1 production

2005 ◽  
Vol 289 (2) ◽  
pp. H813-H822 ◽  
Author(s):  
Maria A. Potenza ◽  
Flora L. Marasciulo ◽  
Delia Mitolo Chieppa ◽  
Giovanni Siro Brigiani ◽  
Gloria Formoso ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endothelial Dysfunction ◽  
Spontaneously Hypertensive Rats ◽  
Ex Vivo ◽  
Pi3 Kinase ◽  
Mesenteric Arteries ◽  
No Production ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Wky Rats

Insulin stimulates production of NO in vascular endothelium via activation of phosphatidylinositol (PI) 3-kinase, Akt, and endothelial NO synthase. We hypothesized that insulin resistance may cause imbalance between endothelial vasodilators and vasoconstrictors (e.g., NO and ET-1), leading to hypertension. Twelve-week-old male spontaneously hypertensive rats (SHR) were hypertensive and insulin resistant compared with control Wistar-Kyoto (WKY) rats (systolic blood pressure 202 ± 11 vs. 132 ± 10 mmHg; fasting plasma insulin 5 ± 1 vs. 0.9 ± 0.1 ng/ml; P < 0.001). In WKY rats, insulin stimulated dose-dependent relaxation of mesenteric arteries precontracted with norepinephrine (NE) ex vivo. This depended on intact endothelium and was blocked by genistein, wortmannin, or Nω-nitro-l-arginine methyl ester (inhibitors of tyrosine kinase, PI3-kinase, and NO synthases, respectively). Vasodilation in response to insulin (but not ACh) was impaired by 20% in SHR (vs. WKY, P < 0.005). Preincubation of arteries with insulin significantly reduced the contractile effect of NE by 20% in WKY but not SHR rats. In SHR, the effect of insulin to reduce NE-mediated vasoconstriction became evident when insulin pretreatment was accompanied by ET-1 receptor blockade (BQ-123, BQ-788). Similar results were observed during treatment with the MEK inhibitor PD-98059. In addition, insulin-stimulated secretion of ET-1 from primary endothelial cells was significantly reduced by pretreatment of cells with PD-98059 (but not wortmannin). We conclude that insulin resistance in SHR is accompanied by endothelial dysfunction in mesenteric vessels with impaired PI3-kinase-dependent NO production and enhanced MAPK-dependent ET-1 secretion. These results may reflect pathophysiology in other vascular beds that directly contribute to elevated peripheral vascular resistance and hypertension.

scholarly journals Aging Additively Influences Insulin- and Insulin-Like Growth Factor-1-Mediated Endothelial Dysfunction and Antioxidant Deficiency in Spontaneously Hypertensive Rats

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 676
Author(s):  
Kunanya Masodsai ◽  
Yi-Yuan Lin ◽  
Sih-Yin Lin ◽  
Chia-Ting Su ◽  
Shin-Da Lee ◽  
...  
Keyword(s):  
Growth Factor ◽  
Endothelial Dysfunction ◽  
Spontaneously Hypertensive Rats ◽  
No Production ◽  
Organ Bath ◽  
Insulin Like Growth Factor ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Nos Inhibitors ◽  
Wistar Kyoto

This study aimed to investigate the aging-related endothelial dysfunction mediated by insulin and insulin-like growth factor-1 (IGF-1) and antioxidant deficiency in hypertension. Male spontaneously hypertensive rats (SHRs) and age-matched normotensive Wistar–Kyoto rats (WKYs) were randomly divided into 24-week-old (younger) and 48-week-old (older) groups, respectively. The endothelial function was evaluated by the insulin- and IGF-1-mediated vasorelaxation of aortic rings via the organ bath system. Serum levels of nitric oxide (NO), malondialdehyde (MDA), catalase, and total antioxidant capacity (TAC) were examined. The insulin- and IGF-1-mediated vasorelaxation was significantly impaired in both 24- and 48-week-old SHRs compared with age-matched WKYs and was significantly worse in the 48-week-old SHR than the 24-week-old SHR. After pretreatments of phosphoinositide 3-kinase (PI3K) or NO synthase (NOS) inhibitors, the insulin- and IGF-1-mediated vasorelaxation became similar among four groups. The serum level of MDA was significantly increased, while the NO, catalase, and TAC were significantly reduced in the 48-week-old SHR compared with the 24-week-old SHR. This study demonstrated that the process of aging additively affected insulin- and IGF-1-mediated endothelial dysfunction in SHRs, which could be partly attributed to the reduced NO production and antioxidant deficiency.

scholarly journals The Sodium-Glucose Cotransporter-2 Inhibitor Canagliflozin Alleviates Endothelial Dysfunction Following In Vitro Vascular Ischemia/Reperfusion Injury in Rats

2021 ◽  
Vol 22 (15) ◽  
pp. 7774
Author(s):  
Sevil Korkmaz-Icöz ◽  
Cenk Kocer ◽  
Alex A. Sayour ◽  
Patricia Kraft ◽  
Mona I. Benker ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Reperfusion Injury ◽  
Vascular Function ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Artery Bypass ◽  
Diabetic Rats ◽  
Organ Bath ◽  
Sodium Glucose Cotransporter

Vascular ischemia/reperfusion injury (IRI) contributes to graft failure and adverse clinical outcomes following coronary artery bypass grafting. Sodium-glucose-cotransporter (SGLT)-2-inhibitors have been shown to protect against myocardial IRI, irrespective of diabetes. We hypothesized that adding canagliflozin (CANA) (an SGLT-2-inhibitor) to saline protects vascular grafts from IRI. Aortic rings from non-diabetic rats were isolated and immediately mounted in organ bath chambers (control, n = 9–10 rats) or underwent cold ischemic preservation in saline, supplemented either with a DMSO vehicle (IR, n = 8–10 rats) or 50µM CANA (IR + CANA, n = 9–11 rats). Vascular function was measured, the expression of 88 genes using PCR-array was analyzed, and feature selection using machine learning was applied. Impaired maximal vasorelaxation to acetylcholine in the IR-group compared to controls was significantly ameliorated by CANA (IR 31.7 ± 3.2% vs. IR + CANA 51.9 ± 2.5%, p < 0.05). IR altered the expression of 17 genes. Ccl2, Ccl3, Ccl4, CxCr4, Fos, Icam1, Il10, Il1a and Il1b have been found to have the highest interaction. Compared to controls, IR significantly upregulated the mRNA expressions of Il1a and Il6, which were reduced by 1.5- and 1.75-fold with CANA, respectively. CANA significantly prevented the upregulation of Cd40, downregulated NoxO1 gene expression, decreased ICAM-1 and nitrotyrosine, and increased PECAM-1 immunoreactivity. CANA alleviates endothelial dysfunction following IRI.

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