Blunted coronary vasodilator response to uridine adenosine tetraphosphate in post-infarct remodeled myocardium is due to reduced P1 receptor activation

Zhou, Zhichao; Wijs-Meijler, Daphne de; Lankhuizen, Inge M.; Jankowski, Joachim; Jankowski, Vera; Danser, A.H. Jan; Duncker, Dirk J.; Merkus, Daphne

doi:10.1016/j.phrs.2013.08.007

Cited by 18 publications

(35 citation statements)

References 38 publications

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“…Furthermore, vasoconstriction was observed in mouse renal arterioles (7) and aorta (8). Although, there is evidence that Up 4 A can produce vasodilation in isolated aortic rings of rats (5), porcine coronary small arteries (11, 12), human and mouse colon (30) as well as induce hypotension in conscious rats (8). All together, these studies suggest that the vascular responses to Up 4 A likely depend on the type of vascular beds and species studied (4).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, Up 4 A induces vasoconstriction in rat perfused kidney through P2X 1 R and P2Y 1 R (10), in rat aorta through P1R and P2XR (5), and in rat pulmonary arteries through P2YR (6), while Up 4 A produces vasodilation in rat perfused kidney through P2Y 1 R and P2Y 2 R (10), in porcine coronary arteries through A 2A AR, P2X 1 R and P2Y 1 R (12) and in human and mouse colon through P2Y 1 R (30). Surprisingly, Up 4 A-mediated vascular contraction in mouse aorta in the present study was not affected by A 3 AR deletion, although one of our previous observations showed that activation of A 3 AR contributes to mouse aortic contraction (19).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, aortic rings of WT were subjected to Up 4 A in the absence and presence of selective A 1 AR antagonist DPCPX (10 nM) (25). To investigate the involvement of P2R in Up 4 A-induced vascular contraction, aortic rings of WT were exposed to Up 4 A in the absence and presence of non-selective P2R antagonist PPADS (10 µM) (12) and selective P2X 1 R antagonist MRS2159 (30 µM) (26), respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Thus, vasoconstriction was observed in rat renal artery through P2X 1 R (3), in rat aorta through P1 and P2XR (5), and in rat pulmonary arteries through P2YR (6). Furthermore, vasoconstriction was also observed in mouse renal arterioles (7), mouse aorta (8) and rat mesenteric arteries (9), although Up 4 A has been subsequently found to be able to exert a vasodilator effect in rat aorta (5), isolated perfused rat kidney (10) and porcine coronary arteries (11, 12) as well as to induce hypotension in conscious rats (8). The observations that plasma concentrations of Up 4 A detected in juvenile hypertensive subjects are elevated (13), as well as intra-aortic injection of Up 4 A increases mean arterial blood pressure in intact animal (3), suggest a role for Up 4 A in the pathogenesis of hypertension.…”

Section: Introductionmentioning

confidence: 99%

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Mechanisms underlying uridine adenosine tetraphosphate-induced vascular contraction in mouse aorta: Role of thromboxane and purinergic receptors

Zhou

Sun

Tilley

et al. 2015

Vascular Pharmacology

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Uridine adenosine tetraphosphate (Up4A), a novel endothelium-derived vasoactive agent, is proposed to play a role in cardiovascular disorders and induces aortic contraction through activation of cyclooxygenases (COX). We and others demonstrated that activation of A1 or A3 adenosine receptors (AR) results in vascular contraction via thromboxane (TX) A2 production. However, the mechanisms of Up4A-induced vascular contraction in mouse aorta are not understood. We hypothesize that Up4A-induced aortic contraction is through COX-derived TXA2 production, which requires activation of A1 and/or A3AR. Concentration responses to Up4A were conducted in isolated aorta. The TXB2 production, a metabolite of TXA2, was also measured. Up4A (10−9–10−5 M) produced a concentration-dependent contraction >70%, which was markedly attenuated by COX and COX1 but not by COX2 inhibition. Notably, Up4A-induced aortic contraction was blunted by both TX synthase inhibitor ozagrel and TXA2 receptor (TP) antagonist SQ29548. Surprisingly, A3AR deletion had no effect on Up4A-induced contraction. Moreover, A1AR deletion or antagonism as well as A1/A3AR deletion potentiated Up4A-induced aortic contraction, suggesting a vasodilator influence of A1AR. In contrast, non-selective purinergic P2 receptor antagonist PPADS significantly blunted Up4A-induced aortic contraction to a similar extent as selective P2X1R antagonist MRS2159, the latter of which was further reduced by addition of ozagrel. Endothelial denudation almost fully attenuated Up4A-induced contraction. Furthermore, Up4A (3 µM) increased TXB2 formation, which was inhibited by either MRS2159 or ozagrel. In conclusion, Up4A-induced aortic contraction depends on activation of TX synthase and TP, which partially requires the activation of P2X1R but not A1 or A3 AR through an endothelium-dependent mechanism.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mechanisms underlying uridine adenosine tetraphosphate-induced vascular contraction in mouse aorta: Role of thromboxane and purinergic receptors

Zhou

Sun

Tilley

et al. 2015

Vascular Pharmacology

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“…14,15 Following a thoracotomy through the fourth left intercostal space, a polyvinyl catheter was inserted into the aorta. The heart was exposed via a small pericardial incision, the proximal left circumflex artery was dissected, and a suture was placed around it.…”

Section: Surgerymentioning

confidence: 99%

UM206, a selective Frizzled antagonist, attenuates adverse remodeling after myocardial infarction in swine

Uitterdijk

Hermans

Wijs-Meijler

et al. 2016

Laboratory Investigation

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Modulation of Wnt/Frizzled signaling with UM206 reduced infarct expansion and prevented heart failure development in mice, an effect that was accompanied by increased myofibroblast presence in the infarct, suggesting that Wnt/Frizzled signaling has a key role in cardiac remodeling following myocardial infarction (MI). This study investigated the effects of modulation of Wnt/Frizzled signaling with UM206 in a swine model of reperfused MI. For this purpose, seven swine with MI were treated with continuous infusion of UM206 for 5 weeks. Six control swine were treated with vehicle. Another eight swine were sham-operated. Cardiac function was determined by echo in awake swine. Infarct mass was estimated at baseline by heart-specific fatty acid-binding protein ELISA and at follow-up using planimetry. Components of Wnt/Frizzled signaling, myofibroblast presence, and extracellular matrix were measured at follow-up with qPCR and/or histology. Results show that UM206 treatment resulted in a significant decrease in infarct mass compared with baseline (−41 ± 10%), whereas infarct mass remained stable in the Control-MI group (+3 ± 17%). Progressive dilation of the left ventricle occurred in the Control-MI group between 3 and 5 weeks after MI, while adverse remodeling was halted in the UM206-treated group. mRNA expression for Frizzled-4 and the Frizzled co-receptor LRP5 was increased in UM206-treated swine as compared with Control-MI swine. Myofibroblast presence was significantly lower in infarcted tissue of the UM206-treated animals (1.53 ± 0.43% vs 3.38 ± 0.61%) at 5 weeks follow-up. This study demonstrates that UM206 treatment attenuates adverse remodeling in a swine model of reperfused MI, indicating that Wnt/Frizzled signaling is a promising target to improve infarct healing and limit post-MI remodeling. Although left ventricular (LV) remodeling after myocardial infarction (MI) is aimed at maintaining cardiac pump function, initial infarct size, and the subsequent progressive expansion and thinning of the infarcted area constitute the main risk factors for the development of post-MI heart failure. 1 Several strategies that influence either the infarct size and/or the ensuing process of LV remodeling have been proposed as potential therapies to halt the development and progression of LV dysfunction. 2,3 Cardiac fibroblasts, which account for up to 70% of the cells present in the myocardium, regulate extracellular matrix (ECM) turnover, and have an essential role in cardiac homeostasis. Fibroblasts are more resistant to ischemia than cardiomyocytes, 4-6 and prolonged myocardial ischemia results in death of particularly the cardiomyocytes, whereas the fibroblasts survive. Fibroblasts have therefore been proposed to be a therapeutic target to influence the healing process of the infarcted myocardium. 1,5,[7][8][9] In addition to these resident fibroblasts, fibroblasts enter the infarcted tissue by migration. When present in the infarcted area, the fibroblasts gradually differentiate into their more contractile and synthetic...

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Temporal Changes in Coronary Hyperemic and Resting Hemodynamic Indices in Nonculprit Vessels of Patients With ST-Segment Elevation Myocardial Infarction

et al. 2019

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IMPORTANCE Percutaneous coronary intervention (PCI) of nonculprit vessels among patients with ST-segment elevation myocardial infarction (STEMI) is associated with improved clinical outcome compared with culprit vessel-only PCI. Fractional flow reserve (FFR) and coronary flow reserve are hyperemic indices used to guide revascularization. Recently, instantaneous wave-free ratio was introduced as a nonhyperemic alternative to FFR. Whether these indices can be used in the acute setting of STEMI continues to be investigated. OBJECTIVE To assess the value of hemodynamic indices in nonculprit vessels of patients with STEMI from the index event to 1-month follow-up. DESIGN, SETTING, AND PARTICIPANTS This substudy of the Reducing Micro Vascular Dysfunction in Revascularized STEMI Patients by Off-target Properties of Ticagrelor (REDUCE-MVI) randomized clinical trial enrolled 98 patients with STEMI who had an angiographic intermediate stenosis in at least 1 nonculprit vessel. Patient enrollment was between May 1, 2015, and September 19, 2017.After successful primary PCI, nonculprit intracoronary hemodynamic measurements were performed and repeated at 1-month follow-up. Cardiac magnetic resonance imaging was performed from 2 to 7 days and 1 month after primary PCI. MAIN OUTCOMES AND MEASURESThe value of nonculprit instantaneous wave-free ratio, FFR, coronary flow reserve, hyperemic index of microcirculatory resistance, and resting microcirculatory resistance from the index event to 1-month follow-up. RESULTSOf 73 patients with STEMI included in the final analysis, 59 (80.8%) were male, with a mean (SD) age of 60.8 (9.9) years. Instantaneous wave-free ratio (SD) did not change significantly (0.93 [0.07] vs 0.94 [0.06]; P = .12) and there was no change in resting distal pressure/aortic pressure (mean [SD], 0.94 [0.06] vs 0.95 [0.06]; P = .25) from the acute moment to 1-month follow-up. The FFR decreased (mean [SD], 0.88 [0.07] vs 0.86 [0.09]; P = .001) whereas coronary flow reserve increased (mean [SD], 2.9 [1.4] vs 4.1 [2.2]; P < .001). Hyperemic index of microcirculatory resistance decreased and resting microcirculatory resistance increased from the acute moment to follow-up. The decrease in distal pressure from rest to hyperemia was smaller at the acute moment vs follow-up (mean [SD], 10.6 [11.2] mm Hg vs 14.1 [14.2] mm Hg; P = .05). This blunted acute hyperemic response correlated with final infarct size (ρ, -0.29; P = .02). The resistive reserve ratio was lower at the acute moment vs follow-up (mean [SD], 3.4 [1.7] vs 5.0 [2.7]; P < .001). CONCLUSIONS AND RELEVANCEIn the acute setting of STEMI, nonculprit coronary flow reserve was reduced and FFR was augmented, whereas instantaneous wave-free ratio was not altered. These results may be explained by an increased hyperemic microvascular resistance and a blunted adenosine responsiveness at the acute moment that was associated with infarct size.

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Blunted coronary vasodilator response to uridine adenosine tetraphosphate in post-infarct remodeled myocardium is due to reduced P1 receptor activation

Cited by 18 publications

References 38 publications

Mechanisms underlying uridine adenosine tetraphosphate-induced vascular contraction in mouse aorta: Role of thromboxane and purinergic receptors

Mechanisms underlying uridine adenosine tetraphosphate-induced vascular contraction in mouse aorta: Role of thromboxane and purinergic receptors

UM206, a selective Frizzled antagonist, attenuates adverse remodeling after myocardial infarction in swine

Temporal Changes in Coronary Hyperemic and Resting Hemodynamic Indices in Nonculprit Vessels of Patients With ST-Segment Elevation Myocardial Infarction

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