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
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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)