Vasodilator Reactive Oxygen Species Ameliorate Perturbed Myocardial Oxygen Delivery in Exercising Swine with Multiple Comorbidities

Overview

Journal Basic Res Cardiol

Specialty Cardiology & Vascular Diseases

Date 2024 May 25

PMID 38796544

Authors

R W A van Drie

J van de Wouw

L M Zandbergen

J Dehairs

J V Swinnen

M T Mulder

M C Verhaar

A Maassenvandenbrink

D J Duncker

O Sorop

D Merkus

Affiliations

Soon will be listed here.

Abstract

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) ET-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 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 (HO) 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 HO acts as vasodilator ROS in the coronary microvasculature. Despite elevated ET-1 plasma levels in DM + HFD + CKD swine, ET 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 HO-mediated coronary vasodilation.

Citing Articles

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References

Heusch G . Coronary blood flow in heart failure: cause, consequence and bystander. Basic Res Cardiol. 2022; 117(1):1. PMC: 8758654. DOI: 10.1007/s00395-022-00909-8. View

Beyer A, Zinkevich N, Miller B, Liu Y, Wittenburg A, Mitchell M . Transition in the mechanism of flow-mediated dilation with aging and development of coronary artery disease. Basic Res Cardiol. 2016; 112(1):5. PMC: 6758541. DOI: 10.1007/s00395-016-0594-x. View

McNally J, Saxena A, Cai H, Dikalov S, Harrison D . Regulation of xanthine oxidoreductase protein expression by hydrogen peroxide and calcium. Arterioscler Thromb Vasc Biol. 2005; 25(8):1623-8. DOI: 10.1161/01.ATV.0000170827.16296.6e. View

Loffredo L, Ivanov V, Ciobanu N, Ivanov M, Ciacci P, Nocella C . Low-grade endotoxemia and NOX2 in patients with coronary microvascular angina. Kardiol Pol. 2022; 80(9):911-918. DOI: 10.33963/KP.a2022.0130. View

Ohanian J, Forman S, Katzenberg G, Ohanian V . Endothelin-1 stimulates small artery VCAM-1 expression through p38MAPK-dependent neutral sphingomyelinase. J Vasc Res. 2012; 49(4):353-62. DOI: 10.1159/000336649. View

Davenport A, Hyndman K, Dhaun N, Southan C, Kohan D, Pollock J . Endothelin. Pharmacol Rev. 2016; 68(2):357-418. PMC: 4815360. DOI: 10.1124/pr.115.011833. View

Crivelli S, van Kruining D, Luo Q, Stevens J, Giovagnoni C, Paulus A . Ceramide analog [F]F-HPA-12 detects sphingolipid disbalance in the brain of Alzheimer's disease transgenic mice by functioning as a metabolic probe. Sci Rep. 2020; 10(1):19354. PMC: 7652882. DOI: 10.1038/s41598-020-76335-4. View

Johnson B, Shaw L, Pepine C, Reis S, Kelsey S, Sopko G . Persistent chest pain predicts cardiovascular events in women without obstructive coronary artery disease: results from the NIH-NHLBI-sponsored Women's Ischaemia Syndrome Evaluation (WISE) study. Eur Heart J. 2006; 27(12):1408-15. DOI: 10.1093/eurheartj/ehl040. View

Kleinbongard P, Lieder H, Skyschally A, Heusch G . No sex-related differences in infarct size, no-reflow, and protection by ischaemic pre-conditioning in Göttingen minipigs. Cardiovasc Res. 2022; 119(2):561-570. DOI: 10.1093/cvr/cvac062. View

10.

Hattori Y, Suzuki M, Hattori S, Kasai K . Globular adiponectin upregulates nitric oxide production in vascular endothelial cells. Diabetologia. 2003; 46(11):1543-9. DOI: 10.1007/s00125-003-1224-3. View

11.

Leong D, Tjoe B, Zarrini P, Cook-Wiens G, Wei J, Shufelt C . Risk factors for heart failure in women with ischemia and no obstructive coronary artery disease. Am Heart J Plus. 2024; 8:100035. PMC: 10978133. DOI: 10.1016/j.ahjo.2021.100035. View

12.

Erdei N, Toth A, Pasztor E, Papp Z, Edes I, Koller A . High-fat diet-induced reduction in nitric oxide-dependent arteriolar dilation in rats: role of xanthine oxidase-derived superoxide anion. Am J Physiol Heart Circ Physiol. 2006; 291(5):H2107-15. DOI: 10.1152/ajpheart.00389.2006. View

13.

Kwan A, Wei J, Ouyang D, Ebinger J, Merz C, Berman D . Sex differences in contributors to coronary microvascular dysfunction. Front Cardiovasc Med. 2023; 10:1085914. PMC: 9902873. DOI: 10.3389/fcvm.2023.1085914. View

14.

van de Wouw J, Broekhuizen M, Sorop O, Joles J, Verhaar M, Duncker D . Chronic Kidney Disease as a Risk Factor for Heart Failure With Preserved Ejection Fraction: A Focus on Microcirculatory Factors and Therapeutic Targets. Front Physiol. 2019; 10:1108. PMC: 6737277. DOI: 10.3389/fphys.2019.01108. View

15.

Pollock D, Pollock J . Endothelin and oxidative stress in the vascular system. Curr Vasc Pharmacol. 2005; 3(4):365-7. DOI: 10.2174/157016105774329408. View

16.

Cantu-Medellin N, Kelley E . Xanthine oxidoreductase-catalyzed reactive species generation: A process in critical need of reevaluation. Redox Biol. 2013; 1:353-8. PMC: 3757702. DOI: 10.1016/j.redox.2013.05.002. View

17.

Borbouse L, Dick G, Payne G, Berwick Z, Neeb Z, Alloosh M . Metabolic syndrome reduces the contribution of K+ channels to ischemic coronary vasodilation. Am J Physiol Heart Circ Physiol. 2010; 298(4):H1182-9. PMC: 2853415. DOI: 10.1152/ajpheart.00888.2009. View

18.

Zhang D, Borbouse L, Gebremedhin D, Mendoza S, Zinkevich N, Li R . H2O2-induced dilation in human coronary arterioles: role of protein kinase G dimerization and large-conductance Ca2+-activated K+ channel activation. Circ Res. 2011; 110(3):471-80. PMC: 3272100. DOI: 10.1161/CIRCRESAHA.111.258871. View

19.

Dick G, Bratz I, Borbouse L, Payne G, Dincer U, Knudson J . Voltage-dependent K+ channels regulate the duration of reactive hyperemia in the canine coronary circulation. Am J Physiol Heart Circ Physiol. 2008; 294(5):H2371-81. DOI: 10.1152/ajpheart.01279.2007. View

20.

Kleinbongard P, Lieder H, Skyschally A, Heusch G . No robust reduction of infarct size and no-reflow by metoprolol pretreatment in adult Göttingen minipigs. Basic Res Cardiol. 2023; 118(1):23. PMC: 10250284. DOI: 10.1007/s00395-023-00993-4. View