Altered purinergic signaling in uridine adenosine tetraphosphate-induced coronary relaxation in swine with metabolic derangement

Purinergic Signalling, May 2017

We previously demonstrated that uridine adenosine tetraphosphate (Up4A) induces potent and partially endothelium-dependent relaxation in the healthy porcine coronary microvasculature. We subsequently showed that Up4A-induced porcine coronary relaxation was impaired via downregulation of P1 receptors after myocardial infarction. In view of the deleterious effect of metabolic derangement on vascular function, we hypothesized that the coronary vasodilator response to Up4A is impaired in metabolic derangement, and that the involvement of purinergic receptor subtypes and endothelium-derived vasoactive factors (EDVFs) is altered. Coronary small arteries, dissected from the apex of healthy swine and swine 6 months after induction of diabetes with streptozotocin and fed a high-fat diet, were mounted on wire myographs. Up4A (10−9–10−5 M)-induced coronary relaxation was maintained in swine with metabolic derangement compared to normal swine, despite impaired endothelium-dependent relaxation to bradykinin and despite blunted P2X7 receptor and NO-mediated vasodilator influences of Up4A. Moreover, a thromboxane-mediated vasoconstrictor influence was unmasked. In contrast, an increased Up4A-mediated vasodilator influence via P2Y1 receptors was observed, while, in response to Up4A, cytochrome P450 2C9 switched from producing vasoconstrictor to vasodilator metabolites in swine with metabolic derangement. Coronary vascular expression of A2A and P2X7 receptors as well as eNOS, as assessed with real-time PCR, was reduced in swine with metabolic derangement. In conclusion, although the overall coronary vasodilator response to Up4A was maintained in swine with metabolic derangement, the involvement of purinergic receptor subtypes and EDVF was markedly altered, revealing compensatory mechanisms among signaling pathways in Up4A-mediated coronary vasomotor influence in the early phase of metabolic derangement. Future studies are warranted to investigate the effects of severe metabolic derangement on coronary responses to Up4A.

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Altered purinergic signaling in uridine adenosine tetraphosphate-induced coronary relaxation in swine with metabolic derangement

Altered purinergic signaling in uridine adenosine tetraphosphate-induced coronary relaxation in swine with metabolic derangement Zhichao Zhou 0 1 2 3 4 5 Oana Sorop 0 1 2 3 4 5 Vincent J. de Beer 0 1 2 3 4 5 Ilkka Heinonen 0 1 2 3 4 5 Caroline Cheng 0 1 2 3 4 5 A. H. Jan Danser 0 1 2 3 4 5 Dirk J. Duncker 0 1 2 3 4 5 Daphne Merkus 0 1 2 3 4 5 0 Present address: Unit of Cardiology, Department of Medicine, Karolinska University Hospital, Karolinska Institutet , Stockholm , Sweden 1 Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus MC, University Medical Center Rotterdam , PO Box 2040, 3000 CA Rotterdam , The Netherlands 2 Division of Pharmacology, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam , Rotterdam , The Netherlands 3 Department of Nephrology & Hypertension, University Medical Center Utrecht , Utrecht , The Netherlands 4 Department of Clinical Physiology and Nuclear Medicine, University of Turku , Turku , Finland 5 Turku PET Centre, University of Turku and Turku University Hospital , Turku , Finland We previously demonstrated that uridine adenosine tetraphosphate (Up4A) induces potent and partially endothelium-dependent relaxation in the healthy porcine coronary microvasculature. We subsequently showed that Up4A-induced porcine coronary relaxation was impaired via downregulation of P1 receptors after myocardial infarction. In view of the deleterious effect of metabolic derangement on vascular function, we hypothesized that the coronary vasodilator response to Up4A is impaired in metabolic derangement, and that the involvement of purinergic receptor subtypes and endothelium-derived vasoactive factors (EDVFs) is altered. Coronary small arteries, dissected from the apex of healthy swine and swine 6 months after induction of diabetes with streptozotocin and fed a high-fat diet, were mounted on wire myographs. Up4A (10−9-10−5 M)- Up4A; Coronary relaxation; Purinergic receptor; Thromboxane; Cytochrome P450 2C9; Metabolic derangement - induced coronary relaxation was maintained in swine with metabolic derangement compared to normal swine, despite impaired endothelium-dependent relaxation to bradykinin and despite blunted P2X7 receptor and NO-mediated vasodilator influences of Up4A. Moreover, a thromboxanemediated vasoconstrictor influence was unmasked. In contrast, an increased Up4A-mediated vasodilator influence via P2Y1 receptors was observed, while, in response to Up4A, cytochrome P450 2C9 switched from producing vasoconstrictor to vasodilator metabolites in swine with metabolic derangement. Coronary vascular expression of A2A and P2X7 receptors as well as eNOS, as assessed with realtime PCR, was reduced in swine with metabolic derangement. In conclusion, although the overall coronary vasodilator response to Up4A was maintained in swine with metabolic derangement, the involvement of purinergic receptor subtypes and EDVF was markedly altered, revealing compensatory mechanisms among signaling pathways in Up4A-mediated coronary vasomotor influence in the early phase of metabolic derangement. Future studies are warranted to investigate the effects of severe metabolic derangement on coronary responses to Up4A. Diabetes mellitus is the most prevalent endocrine disorder worldwide, and diabetes mellitus and associated metabolic derangement constitute an important risk factor for development of cardiovascular disease including atherosclerosis and diabetic heart disease. The latter is the consequence not only of proximal obstructive coronary artery disease but also of coronary microvascular disease [1, 2]. Endothelial dysfunction is an important determinant of altered vascular reactivity and plays a major role in the etiology of diabetes-induced macrovascular and microvascular complications [3, 4]. This endothelial dysfunction encompasses an imbalance between the secretion of endothelium-derived relaxing factors (such as NO and prostacyclin) and endothelium-derived constricting factors (such as endothelin and thromboxane) [4, 5]. Uridine adenosine tetraphosphate (Up4A) was initially identified as an endothelium-derived vasoconstrictor, exerting its constrictor influence in various vascular beds [6–10]. The vasoconstriction was shown to involve the generation of thromboxane [11] and reactive oxygen species [12]. A subsequent study reported that Up4A-mediated vascular contraction was enhanced in renal, basilar, and femoral arteries of DOCAsalt-induced hypertensive rats compared to normal rats [9]. Moreover, Up4A-induced contraction was increased in renal arteries from rats with type 2 diabetes through activation of the cyclooxygenase-thromboxane pathway [13], suggesting that disease states, including diabetes-associated metabolic der a n g e m e n t [ 1 4 ] , m a y a g g r a v a t e U p 4 A - m e d i a t e d vasoconstriction. Similar to other extracellular nucleotides, Up4A exerts its vasomotor influence (...truncated)


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Zhichao Zhou, Oana Sorop, Vincent J. de Beer, Ilkka Heinonen, Caroline Cheng, A. H. Jan Danser, Dirk J. Duncker, Daphne Merkus. Altered purinergic signaling in uridine adenosine tetraphosphate-induced coronary relaxation in swine with metabolic derangement, Purinergic Signalling, 2017, pp. 1-11, DOI: 10.1007/s11302-017-9563-6