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ROS‐NO Signaling is Altered in Exercising Swine with Multiple Comorbidities
Author(s) -
Sorop Oana,
Van De Wouw Jens,
Van Drie Ruben,
Merkus Daphne,
Duncker Dirk J.
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.838.26
Subject(s) - medicine , endocrinology , oxidative stress , endothelial dysfunction , diabetes mellitus , reactive oxygen species , kidney disease , enos , inflammation , nadph oxidase , renal function , nitric oxide , chemistry , nitric oxide synthase , biochemistry
Multiple comorbidities, such as diabetes mellitus (DM), hypercholesterolemia and chronic kidney disease (CKD) induce sustained systemic inflammation and coronary endothelial dysfunction and increased oxidative stress. The resulting alterations in microvascular tone may contribute to impaired myocardial perfusion. Hypothesis Increased production of reactive oxygen species (ROS) due to DM, CKD and high fat diet (HFD) results in loss of NO bioavailability in the coronary microvasculature of exercising swine leading finally to altered myocardial perfusion. Methods and Results In 6 female swine, DM (streptozotocin 3×50mg/kg iv), CKD (renal embolization), and hypercholesterolemia (via high fat diet, HFD) were induced for 6 months (DM+HFD+CKD). 8 female healthy swine on normal pig chow served as controls (CON). The role of ROS‐NO pathways in the regulation of coronary flow regulation was studied at rest and during graded treadmill exercise with/without eNOS inhibition (nitro‐L‐arginine), and ROS scavengers (MPG+Tempol). 6 months after the induction of comorbidities, DM+HFD+CKD animals had hyperglycemia (18.7±1.9 vs 7.5±0.6mmol/L), renal dysfunction (glomerular filtration rate: 123±12 vs 202±8 ml/min), hypercholesterolemia (7.3±0.7 vs 1.7±0.1mmol/l) and sustained systemic inflammation (TNF 51.6±5.1 vs 24.6±5.5pg/ml, all P<0.05). Myocardial superoxide production was increased in DM+HFD+CKD animals due to NADPH oxidase activation and eNOS uncoupling and this was associated with a lower myocardial NO production, (P<0.05). Myocardial oxygen delivery was impaired in DM+HFD+CKD swine at rest and during exercise, resulting in reduced coronary venous oxygen saturation (cvSaO 2 ) compared to CON (P<0.05). eNOS‐inhibition resulted in coronary microvascular constriction in CON, reflected by reduced cvSaO 2 , however, it had no effect in DM+HFD+CKD (Fig. A, B, *P<0.05). Interestingly, scavenging of ROS resulted in decreased cvSaO 2 in DM+HFD+CKD and had no effect in CON (Fig. C, D), suggesting that the increased oxidative stress resulted in increased production of the vasodilator hydrogen peroxide. Conclusion In swine, 6 months exposure to multiple comorbidities resulted in impaired myocardial oxygen delivery mediated by altered NO bioavailability, which was associated with increased oxidative stress. This was partially compensated by increased hydrogen peroxide‐mediated vasodilation. Support or Funding Information This study was supported by a grant from the Netherlands CardioVascular Research Initiative: an initiative with support of the Dutch Heart Foundation [CVON2014‐11 (RECONNECT)] This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .