María S. Avendaño

Reciprocal Relationship Between Reactive Oxygen Species and Cyclooxygenase-2 and Vascular Dysfunction in Hypertension

AIMS This study evaluates a possible relationship between reactive oxygen species (ROS) and cyclooxygenase (COX)-2-derived products in conductance and resistance arteries from hypertensive animals. Angiotensin II (Ang II)-infused mice or spontaneously hypertensive rats treated with the NAD(P)H Oxidase inhibitor apocynin, the mitochondrion-targeted SOD2 mimetic Mito-TEMPO, the superoxide dismutase analog tempol, or the COX-2 inhibitor Celecoxib were used. RESULTS Apocynin, Mito-TEMPO, and Celecoxib treatments prevented Ang II-induced hypertension, the increased vasoconstrictor responses to phenylephrine, and the reduced acetylcholine relaxation. The NOX-2 inhibitor gp91ds-tat, the NOX-1 inhibitor ML171, catalase, and the COX-2 inhibitor NS398 abolished the ex vivo effect of Ang II-enhancing phenylephrine responses. Antioxidant treatments diminished the increased vascular COX-2 expression, prostanoid production, and/or participation of COX-derived contractile prostanoids and thromboxane A(2) receptor (TP) in phenylephrine responses, observed in arteries from hypertensive models. The treatment with the COX-2 inhibitor normalized the increased ROS production (O(2)·(-) and H(2)O(2)), NAD(P)H Oxidase expression (NOX-1, NOX-4, and p22phox) and activity, MnSOD expression, and the participation of ROS in vascular responses in both hypertensive models. Apocynin and Mito-TEMPO also normalized these parameters of oxidative stress. Apocynin, Mito-TEMPO, and Celecoxib improved the diminished nitric oxide (NO) production and the modulation by NO of phenylephrine responses in the Ang II model. INNOVATION This study provides mechanistic evidence of circuitous relationship between COX-2 products and ROS in hypertension. CONCLUSION The excess of ROS from NAD(P)H Oxidase and/or mitochondria and the increased vascular COX-2/TP receptor axis act in concert to induce vascular dysfunction and hypertension.

Aerobic exercise reduces oxidative stress and improves vascular changes of small mesenteric and coronary arteries in hypertension

Regular physical activity is an effective non‐pharmacological therapy for prevention and control of hypertension. We investigated the effects of aerobic exercise training in vascular remodelling and in the mechanical and functional alterations of coronary and small mesenteric arteries from spontaneously hypertensive rats (SHR).

Endothelial dysfunction of rat coronary arteries after exposure to low concentrations of mercury is dependent on reactive oxygen species

BACKGROUND AND PURPOSE Exposure to mercury is known to increase cardiovascular risk but the underlying mechanisms are not well explored. We analysed whether chronic exposure to low mercury doses affects endothelial modulation of the coronary circulation.

Increased Nitric Oxide Bioavailability in Adult GRK2 Hemizygous Mice Protects Against Angiotensin II–Induced Hypertension

G protein–coupled receptor kinase 2 (GRK2) is a ubiquitous serine/threonine protein kinase able to phosphorylate and desensitize the active form of several G protein–coupled receptors. Given the lack of selective inhibitors for GRK2, we investigated the effects elicited by GRK2 inhibition in vascular responses using global adult hemizygous mice (GRK2+/−). The vasodilator responses to acetylcholine or isoproterenol were increased in aortas and mesenteric resistance arteries from GRK2+/− mice compared with wild-type (WT) littermates. After angiotensin II (AngII) infusion, GRK2+/− mice were partially protected against hypertension, vascular remodeling, and mechanical alterations, even when resting basal blood pressures were not significantly different. AngII infusion also (1) increased GRK2 levels in WT but not in GRK2+/− vessels; (2) increased vasoconstrictor responses to phenylephrine in WT but not in GRK2+/− mice; and (3) decreased vasodilator responses to acetylcholine and vascular pAkt and eNOS levels more in WT than in GRK2+/− animals. Vascular NO production and the modulation of vasoconstrictor responses by endothelial-derived NO remained enhanced in GRK2+/− mice infused with AngII. Thus, GRK2+/− mice are resistant to the development of vascular remodeling and mechanical alterations, endothelial dysfunction, increased vasoconstrictor responses, and hypertension induced by AngII at least partially through the preservation of NO bioavailability. In conclusion, our results describe an important role for GRK2 in systemic hypertension and further establish that an inhibition of GRK2 could be a beneficial treatment for this condition.

Role of COX‐2‐derived PGE2 on vascular stiffness and function in hypertension

Prostanoids derived from COX‐2 and EP receptors are involved in vascular remodelling in different cardiovascular pathologies. This study evaluates the contribution of COX‐2 and EP1 receptors to vascular remodelling and function in hypertension.

Aerobic exercise training increases neuronal nitric oxide release and bioavailability and decreases noradrenaline release in mesenteric artery from spontaneously hypertensive rats.

Objective: To study the effect of aerobic exercise training on sympathetic, nitrergic and sensory innervation function in superior mesenteric artery from spontaneously hypertensive rats (SHRs). Methods: De-endothelized vascular rings from sedentary and trained SHRs (treadmill 12 weeks) were used. Vasomotor responses to electrical field stimulation (EFS), noradrenaline, nitric oxide donor DEA-NO and calcitonin gene-related peptide (CGRP) were studied. Neuronal nitric oxide synthase (nNOS) expression and nitric oxide, superoxide anions (O2.-), noradrenaline and CGRP levels were also determined. Results: Aerobic exercise training decreased vasoconstrictor response to EFS but increased noradrenaline response. Phentolamine decreased while N&ohgr;-nitro-L-arginine methyl ester (L-NAME) increased the response to EFS; the effect of both drugs was greater in trained animals. Training also decreased noradrenaline release and O2.- production and increased nNOS expression, nitric oxide release and the vasodilator response to DEA-NO. The O2.- scavenger tempol increased DEA-NO-induced vasodilation only in sedentary rats. The EFS-induced contraction was increased to a similar extent in both experimental groups by preincubation with CGRP (8–37). CGRP release and vasodilator response were not modified by training. Conclusion: Aerobic exercise training decreases contractile response to EFS in mesenteric artery from SHRs. This effect is the net result of decreased noradrenaline release, increased sensitivity to the vasoconstrictive effects of noradrenaline and increased neuronal nitric oxide release and bioavailability. These modifications might contribute to the beneficial effects of aerobic exercise training on blood pressure.

Losartan and tempol treatments normalize the increased response to hydrogen peroxide in resistance arteries from hypertensive rats

Objective To analyse the role of angiotensin II, via AT1 receptors, and oxidative stress in the mechanisms underlying the increased response to hydrogen peroxide (H2O2) of mesenteric resistance arteries from spontaneously hypertensive rats (SHRs). Methods Arteries from normotensive and SHRs untreated or treated with the AT1 receptor antagonist, losartan (15 mg/kg per day, 12 weeks), or with the superoxide dismutase analogue, tempol (1 mmol/l, 17 days), were used. Arteries were mounted in microvascular myographs for isometric tension recording; superoxide anion (O2•−) production was evaluated by dihydroethidium fluorescence, thromboxane A2 production by enzyme immunoassay and plasma nitrite levels by the Griess method. Results H2O2 (1–100 μmol/l) induced higher contractile responses in mesenteric resistance arteries from hypertensive than normotensive rats. In SHRs, losartan and tempol treatments induced the following effects: normalized the increased H2O2 contractile responses observed; modified neither the inhibitory effects of the cyclooxygenase inhibitor, indomethacin [1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1-H-indole-3-acetic acid] (1 μmol/l), and the thromboxane A2/prostaglandin H2 receptor antagonist, SQ 29 548 (1 μmol/l), on H2O2 contraction, nor the increase in thromboxane A2 production in response to H2O2; abolished the increased vascular O2•− production; increased both the potentiatory effect of the nitric oxide inhibitor, N(G)-nitro-L-arginine methyl ester (100 μmol/l), on H2O2 responses and the acetylcholine-induced relaxation. Moreover, losartan treatment abolished the effect of the O2•− scavenger, tiron (1 mmol/l), on H2O2 responses and increased plasma nitrite levels. Conclusion Nitric oxide removal by an excessive O2•− production, probably from an upregulated renin–angiotensin system, participates in the increased response to H2O2 in mesenteric resistance arteries from SHRs.

HuR mediates the synergistic effects of angiotensin II and IL‐1β on vascular COX‐2 expression and cell migration

Angiotensin II (AngII) and IL‐1β are involved in cardiovascular diseases through the induction of inflammatory pathways. HuR is an adenylate‐ and uridylate‐rich element (ARE)‐binding protein involved in the mRNA stabilization of many genes. This study investigated the contribution of HuR to the increased expression of COX‐2 induced by AngII and IL‐1β and its consequences on VSMC migration and remodelling.

Lysyl Oxidase Induces Vascular Oxidative Stress and Contributes to Arterial Stiffness and Abnormal Elastin Structure in Hypertension: Role of p38MAPK

AIMS Vascular stiffness, structural elastin abnormalities, and increased oxidative stress are hallmarks of hypertension. Lysyl oxidase (LOX) is an elastin crosslinking enzyme that produces H2O2 as a by-product. We addressed the interplay between LOX, oxidative stress, vessel stiffness, and elastin. RESULTS Angiotensin II (Ang II)-infused hypertensive mice and spontaneously hypertensive rats (SHR) showed increased vascular LOX expression and stiffness and an abnormal elastin structure. Mice over-expressing LOX in vascular smooth muscle cells (TgLOX) exhibited similar mechanical and elastin alterations to those of hypertensive models. LOX inhibition with β-aminopropionitrile (BAPN) attenuated mechanical and elastin alterations in TgLOX mice, Ang II-infused mice, and SHR. Arteries from TgLOX mice, Ang II-infused mice, and/or SHR exhibited increased vascular H2O2 and O2.- levels, NADPH oxidase activity, and/or mitochondrial dysfunction. BAPN prevented the higher oxidative stress in hypertensive models. Treatment of TgLOX and Ang II-infused mice and SHR with the mitochondrial-targeted superoxide dismutase mimetic mito-TEMPO, the antioxidant apocynin, or the H2O2 scavenger polyethylene glycol-conjugated catalase (PEG-catalase) reduced oxidative stress, vascular stiffness, and elastin alterations. Vascular p38 mitogen-activated protein kinase (p38MAPK) activation was increased in Ang II-infused and TgLOX mice and this effect was prevented by BAPN, mito-TEMPO, or PEG-catalase. SB203580, the p38MAPK inhibitor, normalized vessel stiffness and elastin structure in TgLOX mice. INNOVATION We identify LOX as a novel source of vascular reactive oxygen species and a new pathway involved in vascular stiffness and elastin remodeling in hypertension. CONCLUSION LOX up-regulation is associated with enhanced oxidative stress that promotes p38MAPK activation, elastin structural alterations, and vascular stiffness. This pathway contributes to vascular abnormalities in hypertension. Antioxid. Redox Signal. 27, 379-397.

Aldosterone alters the participation of endothelial factors in noradrenaline vasoconstriction differently in resistance arteries from normotensive and hypertensive rats

This study analyzed the effect of aldosterone (0.05mg/kg per day, 3 weeks) on vasoconstriction induced by noradrenaline in mesenteric resistance arteries from WKY rats and SHR. Contraction to noradrenaline was measured in mesenteric resistance arteries from untreated and aldosterone-treatedrats from both strains. Participation of nitric oxide (NO), superoxide anions, thromboxane A(2) (TxA(2)) and prostacyclin in this response was determined. 6-keto-prostaglandin (PG)F1alpha and thromboxane B(2) (TxB(2)) releases were determined by enzyme immunoassay. NO and superoxide anion release were also determined by fluorescence and chemiluminiscence, respectively. Aldosterone did not modify noradrenaline-induced contraction in either strain. In mesenteric resistance arteries from both aldosterone-treated groups, endothelium removal or preincubation with NO synthesis inhibitor L-NAME increased the noradrenaline-induced contraction, while incubation with the superoxide anion scavenger tempol decreased it. Preincubation with either the COX-1/2 or COX-2 inhibitor (indomethacin and NS-398, respectively) decreased the noradrenaline contraction in aldosterone-treated animals, while this response was not modified by COX-1 inhibitor SC-560. TxA(2) synthesis inhibitor (furegrelate), or TxA2 receptor antagonist (SQ 29 548) also decreased the noradrenaline contraction in aldosterone-treated animals. In untreated SHR, but not WKY rats, this response was increased by L-NAME, and reduced by tempol, indomethacin, NS-398 or SQ 29 548. Aldosterone treatment did not modify NO or TxB(2) release, but it did increase superoxide anion and 6-keto-PGF(1alpha) release in mesenteric resistance arteries from both strains. In conclusion, chronic aldosterone treatment reduces smooth muscle contraction to alpha-adrenergic stimuli, producing a new balance in the release of endothelium-derived prostanoids and NO.