Reduced nitric oxide bioavailability impairs myocardial oxygen balance during exercise in swine with multiple risk factors

Wouw, Jens van de; Sorop, Oana; Drie, Ruben W. A. van; Joles, Jaap A.; Danser, A.H. Jan; Verhaar, Marianne C.; Merkus, Daphne; Duncker, Dirk J.

doi:10.1007/s00395-021-00890-8

Cited by 10 publications

(1 citation statement)

References 75 publications

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“…Increased plasma levels of sRAGE are associated with a reduction in AF recurrence after pulmonary vein isolation in diabetic patients [25,61] and inhibitors of AGE formation have been shown to prevent atrial structural remodeling in diabetic rat models [22,63]. Appropriately, multiple risk factors found in metabolic syndrome are known to predispose to ventricular remodeling [27,57]. In previous studies, RDN prevented left ventricular interstitial remodeling in a rat model with metabolic syndrome, hypertension and with coexistent renal insufficiency (Spontaneously Hypertensive Obese rats, SHRob) [29,45].…”

Section: Introductionmentioning

confidence: 99%

Renal denervation reduces atrial remodeling in hypertensive rats with metabolic syndrome

et al. 2022

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Atrial fibrillation (AF) is highly prevalent in hypertensive patients with metabolic syndrome and is related to inflammation and activation of the sympathoadrenergic system. The multi-ligand Receptor-for-Advanced-Glycation-End-products (RAGE) activates inflammation-associated tissue remodeling and is regulated by the sympathetic nervous system. Its counterpart, soluble RAGE (sRAGE), serves as anti-inflammatory decoy receptor with protective properties. We investigated the effect of sympathetic modulation by renal denervation (RDN) on atrial remodeling, RAGE/sRAGE and RAGE ligands in metabolic syndrome. RDN was performed in spontaneously hypertensive obese rats (SHRob) with metabolic syndrome compared with lean spontaneously hypertensive rats (SHR) and with normotensive non-obese control rats. Blood pressure and heart rate were measured by telemetry. The animals were killed 12 weeks after RDN. Left atrial (LA) and right atrial (RA) remodeling was assessed by histological analysis and collagen types. Sympathetic innervation was measured by tyrosine hydroxylase staining of atrial nerve fibers, RAGE/sRAGE, RAGE ligands, cytokine expressions and inflammatory infiltrates were analyzed by Western blot and immunofluorescence staining. LA sympathetic nerve fiber density was higher in SHRob (+44%) versus controls and reduced after RDN (-64% versus SHRob). RAGE was increased (+718%) and sRAGE decreased (− 62%) in SHRob as compared with controls. RDN reduced RAGE expression (− 61% versus SHRob), significantly increased sRAGE levels (+162%) and induced a significant decrease in RAGE ligand levels in SHRob (− 57% CML and − 51% HMGB1) with reduced pro-inflammatory NFkB activation (− 96%), IL-6 production (− 55%) and reduced inflammatory infiltrates. This led to a reduction in atrial fibrosis (− 33%), collagen type I content (− 72%), accompanied by reduced LA myocyte hypertrophy (− 21%). Transfection experiments on H9C2 cardiomyoblasts demonstrated that RAGE is directly involved in fibrosis formation by influencing cellular production of collagen type I. In conclusion, suppression of renal sympathetic nerve activity by RDN prevents atrial remodeling in metabolic syndrome by reducing atrial sympathetic innervation and by modulating RAGE/sRAGE balance and reducing pro-inflammatory and pro-fibrotic RAGE ligands, which provides a potential therapeutic mechanism to reduce the development of AF.

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Section: Introductionmentioning

confidence: 99%

Renal denervation reduces atrial remodeling in hypertensive rats with metabolic syndrome

et al. 2022

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Vasodilator reactive oxygen species ameliorate perturbed myocardial oxygen delivery in exercising swine with multiple comorbidities

van Drie,

van de Wouw,

Zandbergen

et al. 2024

Basic Res Cardiol

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Multiple common cardiovascular comorbidities produce coronary microvascular dysfunction. We previously observed in swine that a combination of diabetes mellitus (DM), high fat diet (HFD) and chronic kidney disease (CKD) induced systemic inflammation, increased oxidative stress and produced coronary endothelial dysfunction, altering control of coronary microvascular tone via loss of NO bioavailability, which was associated with an increase in circulating endothelin (ET). In the present study, we tested the hypotheses that (1) ROS scavenging and (2) ETA+B-receptor blockade improve myocardial oxygen delivery in the same female swine model. Healthy female swine on normal pig chow served as controls (Normal). Five months after induction of DM (streptozotocin, 3 × 50 mg kg−1 i.v.), hypercholesterolemia (HFD) and CKD (renal embolization), swine were chronically instrumented and studied at rest and during exercise. Sustained hyperglycemia, hypercholesterolemia and renal dysfunction were accompanied by systemic inflammation and oxidative stress. In vivo ROS scavenging (TEMPOL + MPG) reduced myocardial oxygen delivery in DM + HFD + CKD swine, suggestive of a vasodilator influence of endogenous ROS, while it had no effect in Normal swine. In vitro wire myography revealed a vasodilator role for hydrogen peroxide (H2O2) in isolated small coronary artery segments from DM + HFD + CKD, but not Normal swine. Increased catalase activity and ceramide production in left ventricular myocardial tissue of DM + HFD + CKD swine further suggest that increased H2O2 acts as vasodilator ROS in the coronary microvasculature. Despite elevated ET-1 plasma levels in DM + HFD + CKD swine, ETA+B blockade did not affect myocardial oxygen delivery in Normal or DM + HFD + CKD swine. In conclusion, loss of NO bioavailability due to 5 months exposure to multiple comorbidities is partially compensated by increased H2O2-mediated coronary vasodilation.

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Physical Activity and Mortality in Patients with Coronary Artery Disease

Fadah

Payan-Schober

2023

Curr Cardiol Rep

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Reduced nitric oxide bioavailability impairs myocardial oxygen balance during exercise in swine with multiple risk factors

Cited by 10 publications

References 75 publications

Renal denervation reduces atrial remodeling in hypertensive rats with metabolic syndrome

Renal denervation reduces atrial remodeling in hypertensive rats with metabolic syndrome

Vasodilator reactive oxygen species ameliorate perturbed myocardial oxygen delivery in exercising swine with multiple comorbidities

Physical Activity and Mortality in Patients with Coronary Artery Disease

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