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Adenosine Metabolism-Key Targets in Cardiovascular Pharmacology

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (25 September 2023) | Viewed by 18461

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Dr. Barbara Kutryb-Zaja̧c

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Guest Editor

Department of Biochemistry, Medical University of Gdansk, 80-211 Gdansk, Poland
Interests: endothelium; atherosclerosis; inflammation; adenosine; nucleotides; adenosine deaminase

Special Issue Information

Dear Colleagues,

Adenosine is an endogenous nucleoside that regulates many physiological functions, especially in the heart and cardiovascular system. Adenosine is derived from either the intracellular or the extracellular dephosphorylation of ATP, the latter involving ecto-enzymes CD39 and CD73. In the cardiovascular system, cells release ATP under hypoxia, inflammation, and cellular stress conditions, occasionally involving specific membrane channels, leading to the generation of adenosine, which confers protection against tissue damage. Intracellularly, adenosine may also be formed in the methionine-related transmethylation pathway as the product of S-adenosylhomocyteine hydrolase, together with homocysteine, an independent cardiovascular risk factor. Adenosine can be deaminated to inosine by cytosolic or ecto adenosine deaminase (ADA). In addition to its enzymatic function, cell-surface ADA plays an extra-enzymatic role in the interactions between cells that expressed ADA-anchoring proteins, providing co-stimulatory signals. Extracellularly, adenosine acts as a signaling molecule by interacting with specific cell surface receptors (A1, A2A, A2B, and A3 adenosine receptors).

Among the cardioprotective properties of adenosine are its ability to improve cholesterol homeostasis, block platelet aggregation, and inhibit the inflammatory response. Cellular and plasma adenosine levels are also controlled by its transmembrane transport, which is mediated by nucleoside transporters. The effectiveness of this transport system is particularly evident in humans, whose blood demonstrates an extremely short half-life of adenosine.

Pharmacological modulations of intra- and extracellular adenosine signaling may be recognized as a valuable therapeutic approach for many cardiovascular pathologies, including atherosclerosis, myocardial ischemia-reperfusion injury, hypertension, thrombosis, and diabetes. This Special Issue will explore in depth the role of adenosine metabolism pathways and their association with cardiovascular diseases. Review and original articles associated with any relevant fields of study are welcome. Potential topics include, but are not limited to, the following:

Intracellular and extracellular adenosine metabolism pathways;
Targeting adenosine-mediated actions at cellular levels;
Adenosine as a treatment for myocardial preservation;
Inhibitors and activators of adenosine metabolism enzymes;
Molecular biology of adenosine signaling;
Bioinformatics of adenosine receptors;
Adenosine metabolism in atherosclerosis;
Adenosine metabolism in endothelial dysfunction;
Adenosine metabolism in inflammation and cholesterol homeostasis;
Anti-platelet effects of adenosine-regulated pathways;
Adenosine-deaminase-anchoring proteins;
Adenosine-converting enzymes as ideal physiologic biomarkers;
Deficiency of adenosine deaminase 2;
Nucleoside transporter pharmacotherapy.

Dr. Barbara Kutryb-Zaja̧c
Guest Editor

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Keywords

adenosine
nucleotides
purinergic signaling
adenosine receptors
atherosclerosis
endothelium
endothelial dysfunction
inflammation
heart failure

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Published Papers (9 papers)

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Editorial

Jump to: Research

4 pages, 192 KiB

Open AccessEditorial

Editorial for the Special Issue Titled “Adenosine Metabolism: Key Targets in Cardiovascular Pharmacology”

by Barbara Kutryb-Zając

Pharmaceuticals 2024, 17(6), 751; https://doi.org/10.3390/ph17060751 - 7 Jun 2024

Viewed by 724

Abstract

Adenine nucleotides and adenosine maintain cardiovascular homeostasis, producing diverse effects by intracellular and extracellular mechanisms [...] Full article

(This article belongs to the Special Issue Adenosine Metabolism-Key Targets in Cardiovascular Pharmacology)

Research

Jump to: Editorial

19 pages, 6100 KiB

Open AccessArticle

Pharmacological Nature of the Purinergic P2Y Receptor Subtypes That Participate in the Blood Pressure Changes Produced by ADPβS in Rats

by Roberto C. Silva-Velasco, Belinda Villanueva-Castillo, Kristian A. Haanes, Antoinette MaassenVanDenBrink and Carlos M. Villalón

Pharmaceuticals 2023, 16(12), 1683; https://doi.org/10.3390/ph16121683 - 3 Dec 2023

Viewed by 1408

Abstract

Purine nucleosides (adenosine) and nucleotides such as adenosine mono/di/triphosphate (AMP/ADP/ATP) may produce complex cardiovascular responses. For example, adenosine-5′-(β-thio)-diphosphate (ADPβS; a stable synthetic analogue of ADP) can induce vasodilatation/vasodepressor responses by endothelium-dependent and independent mechanisms involving purinergic P2Y receptors; however, the specific subtypes participating in these responses remain unknown. Therefore, this study investigated the receptor subtypes mediating the blood pressure changes induced by intravenous bolus of ADPβS in male Wistar rats in the absence and presence of central mechanisms with the antagonists MRS2500 (P2Y₁), PSB0739 (P2Y₁₂), and MRS2211 (P2Y₁₃). For this purpose, 120 rats were divided into 60 anaesthetised rats and 60 pithed rats, and further subdivided into four groups (n = 30 each), namely: (a) anaesthetised rats, (b) anaesthetised rats with bilateral vagotomy, (c) pithed rats, and (d) pithed rats continuously infused (intravenously) with methoxamine (an α₁-adrenergic agonist that restores systemic vascular tone). We observed, in all four groups, that the immediate decreases in diastolic blood pressure produced by ADPβS were exclusively mediated by peripheral activation of P2Y₁ receptors. Nevertheless, the subsequent increases in systolic blood pressure elicited by ADPβS in pithed rats infused with methoxamine probably involved peripheral activation of P2Y₁, P2Y₁₂, and P2Y₁₃ receptors. Full article

(This article belongs to the Special Issue Adenosine Metabolism-Key Targets in Cardiovascular Pharmacology)

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12 pages, 1413 KiB

Open AccessArticle

Endothelial Effects of Simultaneous Expression of Human HO-1, E5NT, and ENTPD1 in a Mouse

by Paulina Mierzejewska, Noemi Di Marzo, Magdalena A. Zabielska-Kaczorowska, Iga Walczak, Ewa M. Slominska, Marialuisa Lavitrano, Roberto Giovannoni, Barbara Kutryb-Zajac and Ryszard T. Smolenski

Pharmaceuticals 2023, 16(10), 1409; https://doi.org/10.3390/ph16101409 - 4 Oct 2023

Viewed by 1372

Abstract

The vascular endothelium is key target for immune and thrombotic responses that has to be controlled in successful xenotransplantation. Several genes were identified that, if induced or overexpressed, help to regulate the inflammatory response and preserve the transplanted organ function and metabolism. However, few studies addressed combined expression of such genes. The aim of this work was to evaluate in vivo the effects of the simultaneous expression of three human genes in a mouse generated using the multi-cistronic F2A technology. Male 3-month-old mice that express human heme oxygenase 1 (hHO-1), ecto-5′-nucleotidase (hE5NT), and ecto-nucleoside triphosphate diphosphohydrolase 1 (hENTPD1) (Transgenic) were compared to wild-type FVB mice (Control). Background analysis include extracellular nucleotide catabolism enzymes profile on the aortic surface, blood nucleotide concentration, and serum L-arginine metabolites. Furthermore, inflammatory stress induced by LPS in transgenic and control mice was used to characterize interleukin 6 (IL-6) and adhesion molecules endothelium permeability responses. Transgenic mice had significantly higher rates of extracellular adenosine triphosphate and adenosine monophosphate hydrolysis on the aortic surface in comparison to control. Increased levels of blood AMP and adenosine were also noticed in transgenics. Moreover, transgenic animals demonstrated the decrease in serum monomethyl-L-arginine level and a higher L-arginine/monomethyl-L-arginine ratio. Importantly, significantly decreased serum IL-6, and adhesion molecule levels were observed in transgenic mice in comparison to control after LPS treatment. Furthermore, reduced endothelial permeability in the LPS-treated transgenic mice was noted as compared to LPS-treated control. The human enzymes (hHO-1, hE5NT, hENTPD1) simultaneously encoded in transgenic mice demonstrated benefits in several biochemical and functional aspects of endothelium. This is consistent in use of this approach in the context of xenotransplantation. Full article

(This article belongs to the Special Issue Adenosine Metabolism-Key Targets in Cardiovascular Pharmacology)

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22 pages, 4073 KiB

Open AccessArticle

Nonselective and A2a-Selective Inhibition of Adenosine Receptors Modulates Renal Perfusion and Excretion Depending on the Duration of Streptozotocin-Induced Diabetes in Rats

by Joanna Dorota Sitek, Marta Kuczeriszka, Agnieszka Walkowska, Elżbieta Kompanowska-Jezierska and Leszek Dobrowolski

Pharmaceuticals 2023, 16(5), 732; https://doi.org/10.3390/ph16050732 - 11 May 2023

Cited by 1 | Viewed by 1770

Abstract

Long-lasting hyperglycaemia may alter the role of adenosine-dependent receptors (P1R) in the control of kidney function. We investigated how P1R activity affects renal circulation and excretion in diabetic (DM) and normoglycaemic (NG) rats; the receptors’ interactions with bioavailable NO and H₂O₂ were also explored. The effects of adenosine deaminase (ADA, nonselective P1R inhibitor) and P1A2a-R-selective antagonist (CSC) were examined in anaesthetised rats, both after short-lasting (2-weeks, DM-14) and established (8-weeks, DM-60) streptozotocin-induced hyperglycaemia, and in normoglycaemic age-matched animals (NG-14, NG-60, respectively). The arterial blood pressure, perfusion of the whole kidney and its regions (cortex, outer-, and inner medulla), and renal excretion were determined, along with the in situ renal tissue NO and H₂O₂ signals (selective electrodes). The ADA treatment helped to assess the P1R-dependent difference in intrarenal baseline vascular tone (vasodilation in DM and vasoconstriction in NG rats), with the difference being more pronounced between DM-60 and NG-60 animals. The CSC treatment showed that in DM-60 rats, A2aR-dependent vasodilator tone was modified differently in individual kidney zones. Renal excretion studies after the ADA and CSC treatments showed that the balance of the opposing effects of A2aRs and other P1Rs on tubular transport, seen in the initial phase, was lost in established hyperglycaemia. Regardless of the duration of the diabetes, we observed a tonic effect of A2aR activity on NO bioavailability. Dissimilarly, the involvement of P1R in tissue production of H₂O₂, observed in normoglycaemia, decreased. Our functional study provides new information on the changing interaction of adenosine in the kidney, as well as its receptors and NO and H₂O₂, in the course of streptozotocin diabetes. Full article

(This article belongs to the Special Issue Adenosine Metabolism-Key Targets in Cardiovascular Pharmacology)

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13 pages, 2562 KiB

Open AccessArticle

Hidden Pool of Cardiac Adenine Nucleotides That Controls Adenosine Production

by Magdalena A. Zabielska-Kaczorowska, Alicja Braczko, Iwona Pelikant-Malecka, Ewa M. Slominska and Ryszard T. Smolenski

Pharmaceuticals 2023, 16(4), 599; https://doi.org/10.3390/ph16040599 - 15 Apr 2023

Cited by 1 | Viewed by 1876

Abstract

Myocardial ischemic adenosine production decreases in subsequent events that may blunt its protective functions. To test the relation between total or mitochondrial cardiac adenine nucleotide pool (TAN) on the energy status with adenosine production, Langendorff perfused rat hearts were subjected to three protocols: 1 min ischemia at 40 min, 10 min ischemia at 50 min, and 1 min ischemia at 85 min in Group I; additional infusion of adenosine (30 µM) for 15 min after 10 min ischemia in Group I-Ado, and 1 min ischemia at 40 and 85 min in the controls (Group No I). A ³¹P NMR and an HPLC were used for the analysis of nucleotide and catabolite concentrations in the heart and coronary effluent. Cardiac adenosine production in Group I measured after 1 min ischemia at 85 min decreased to less than 15% of that at 40 min in Group I, accompanied by a decrease in cardiac ATP and TAN to 65% of the initial results. Adenosine production at 85 min was restored to 45% of that at 40 min in Group I-Ado, accompanied by a rebound of ATP and TAN by 10% vs. Group I. Mitochondrial TAN and free AMP concentrations paralleled that of total cardiac TAN. Changes in energy equilibrium or mitochondrial function were minor. This study highlights that only a fraction of the cardiac adenine nucleotide pool is available for adenosine production, but further studies are necessary to clarify its nature. Full article

(This article belongs to the Special Issue Adenosine Metabolism-Key Targets in Cardiovascular Pharmacology)

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20 pages, 2520 KiB

Open AccessArticle

Cardioprotective Effect of Flibanserin against Isoproterenol-Induced Myocardial Infarction in Female Rats: Role of Cardiac 5-HT2A Receptor Gene/5-HT/Ca²⁺ Pathway

by Mohamed I. Ahmed, Heba M. A. Abdelrazek, Yasser M. Moustafa, Samar Z. Alshawwa, Maysa A. Mobasher, Basel A. Abdel-Wahab, Fathy Elsayed Abdelgawad and Dina M. Khodeer

Pharmaceuticals 2023, 16(4), 502; https://doi.org/10.3390/ph16040502 - 28 Mar 2023

Cited by 5 | Viewed by 3129

Abstract

Myocardial infarction (MI) is a life-threatening ischemic disease and is one of the leading causes of morbidity and mortality worldwide. Serotonin (5-HT) release during myocardial ischemia plays an important role in the progression of myocardial cellular injury. This study was conducted to investigate the possible cardioprotective effect of flibanserin (FLP) against isoproterenol (ISO)-induced MI in rats. Rats were randomly divided into five groups and were treated orally (p.o.) with FLP (15, 30, and 45 mg/kg) for 28 days. ISO was administered subcutaneously (S.C.) (85 mg/kg) on the 27th and 28th days to induce MI. ISO-induced myocardial infarcted rats exhibited a significant increase in cardiac markers, oxidative stress markers, cardiac and serum 5-HT levels, and total cardiac calcium (Ca²⁺) concentration. ISO-induced myocardial infarcted rats also revealed a remarkable alteration of electrocardiogram (ECG) pattern and significantly upregulated expression of the 5-Hydroxytryptamine 2A (5-HT2A) receptors gene. Moreover, ISO-induced myocardial infarcted rats showed significant histopathological findings of MI and hypertrophic signs. However, pretreatment with FLP significantly attenuated the ISO-induced MI in a dose-dependent manner, as the effect of FLP (45 mg/kg) was more pronounced than that of the other two doses, FLP (15 and 30 mg/kg). The present study provides evidence for the cardioprotective efficacy of FLP against ISO-induced MI in rats. Full article

(This article belongs to the Special Issue Adenosine Metabolism-Key Targets in Cardiovascular Pharmacology)

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22 pages, 3445 KiB

Open AccessArticle

Pharmacological Profile of the Purinergic P2Y Receptors That Modulate, in Response to ADPβS, the Vasodepressor Sensory CGRPergic Outflow in Pithed Rats

by Alejandro D. Miguel-Martínez, Juan Linares-Bedolla, Belinda Villanueva-Castillo, Kristian A. Haanes, Antoinette MaassenVanDenBrink and Carlos M. Villalón

Pharmaceuticals 2023, 16(3), 475; https://doi.org/10.3390/ph16030475 - 22 Mar 2023

Cited by 1 | Viewed by 2190

Abstract

Calcitonin gene-related peptide (CGRP), an endogenous neuropeptide released from perivascular sensory nerves, exerts a powerful vasodilatation. Interestingly, adenosine triphosphate (ATP) stimulates the release of CGRP by activation of prejunctional P2X_2/3 receptors, and adenosine 5′-O-2-thiodiphosphate (ADPβS), a stable adenosine diphosphate (ADP) analogue, produces vasodilator/vasodepressor responses by endothelial P2Y₁ receptors. Since the role of ADP in the prejunctional modulation of the vasodepressor sensory CGRPergic drive and the receptors involved remain unknown, this study investigated whether ADPβS inhibits this CGRPergic drive. Accordingly, 132 male Wistar rats were pithed and subsequently divided into two sets. In set 1, ADPβS (5.6 and 10 µg/kg·min) inhibited the vasodepressor CGRPergic responses by electrical stimulation of the spinal T₉–T₁₂ segment. This inhibition by ADPβS (5.6 µg/kg·min) was reverted after i.v. administration of the purinergic antagonists MRS2500 (300 µg/kg; P2Y₁) or MRS2211 (3000 µg/kg; P2Y₁₃), but not by PSB0739 (300 µg/kg; P2Y₁₂), MRS2211 (1000 µg/kg; P2Y₁₃) or the K_ATP blocker glibenclamide (20 mg/kg). In set 2, ADPβS (5.6 µg/kg·min) failed to modify the vasodepressor responses to exogenous α-CGRP. These results suggest that ADPβS inhibits CGRP release in perivascular sensory nerves. This inhibition, apparently unrelated to activation of ATP-sensitive K⁺ channels, involves P2Y₁ and probably P2Y₁₃, but not P2Y₁₂ receptors. Full article

(This article belongs to the Special Issue Adenosine Metabolism-Key Targets in Cardiovascular Pharmacology)

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16 pages, 3485 KiB

Open AccessArticle

Cyclocreatine Phosphate: A Novel Bioenergetic/Anti-Inflammatory Drug That Resuscitates Poorly Functioning Hearts and Protects against Development of Heart Failure

by Salwa A. Elgebaly, Charles Van Buren, Robert Todd, Robert Poston, Reem K. Arafa, Nashwa El-Khazragy, Donald Kreutzer, Mostafa A. Rabie, Ahmed F. Mohamed, Lamiaa A. Ahmed and Nesrine S. El Sayed

Pharmaceuticals 2023, 16(3), 453; https://doi.org/10.3390/ph16030453 - 16 Mar 2023

Cited by 3 | Viewed by 2643

Abstract

Irreversible myocardial injury causes the exhaustion of cellular adenosine triphosphate (ATP) contributing to heart failure (HF). Cyclocreatine phosphate (CCrP) was shown to preserve myocardial ATP during ischemia and maintain cardiac function in various animal models of ischemia/reperfusion. We tested whether CCrP administered prophylactically/therapeutically prevents HF secondary to ischemic injury in an isoproterenol (ISO) rat model. Thirty-nine rats were allocated into five groups: control/saline, control/CCrP, ISO/saline (85 and 170 mg/kg/day s.c. for 2 consecutive days), and ISO/CCrP (0.8 g/kg/day i.p.) either administrated 24 h or 1 h before ISO administration (prophylactic regimen) or 1 h after the last ISO injection (therapeutic regimen) and then daily for 2 weeks. CCrP protected against ISO-induced CK-MB elevation and ECG/ST changes when administered prophylactically or therapeutically. CCrP administered prophylactically decreased heart weight, hs-TnI, TNF-α, TGF-β, and caspase-3, as well as increased EF%, eNOS, and connexin-43, and maintained physical activity. Histology indicated a marked decrease in cardiac remodeling (fibrin and collagen deposition) in the ISO/CCrP rats. Similarly, therapeutically administered CCrP showed normal EF% and physical activity, as well as normal serum levels of hs-TnI and BNP. In conclusion, the bioenergetic/anti-inflammatory CCrP is a promising safe drug against myocardial ischemic sequelae, including HF, promoting its clinical application to salvage poorly functioning hearts. Full article

(This article belongs to the Special Issue Adenosine Metabolism-Key Targets in Cardiovascular Pharmacology)

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14 pages, 2160 KiB

Open AccessArticle

Regulation of Hypoxic–Adenosinergic Signaling by Estrogen: Implications for Microvascular Injury

by Jessica Cassavaugh, Nada Qureshi, Eva Csizmadia, Maria Serena Longhi, Robina Matyal and Simon C. Robson

Pharmaceuticals 2023, 16(3), 422; https://doi.org/10.3390/ph16030422 - 10 Mar 2023

Cited by 2 | Viewed by 2123

Abstract

Loss of estrogen, as occurs with normal aging, leads to increased inflammation, pathologic angiogenesis, impaired mitochondrial function, and microvascular disease. While the influence of estrogens on purinergic pathways is largely unknown, extracellular adenosine, generated at high levels by CD39 and CD73, is known to be anti-inflammatory in the vasculature. To further define the cellular mechanisms necessary for vascular protection, we investigated how estrogen modulates hypoxic–adenosinergic vascular signaling responses and angiogenesis. Expression of estrogen receptors, purinergic mediators inclusive of adenosine, adenosine deaminase (ADA), and ATP were measured in human endothelial cells. Standard tube formation and wound healing assays were performed to assess angiogenesis in vitro. The impacts on purinergic responses in vivo were modeled using cardiac tissue from ovariectomized mice. CD39 and estrogen receptor alpha (ERα) levels were markedly increased in presence of estradiol (E2). Suppression of ERα resulted in decreased CD39 expression. Expression of ENT1 was decreased in an ER-dependent manner. Extracellular ATP and ADA activity levels decreased following E2 exposure while levels of adenosine increased. Phosphorylation of ERK1/2 increased following E2 treatment and was attenuated by blocking adenosine receptor (AR) and ER activity. Estradiol boosted angiogenesis, while inhibition of estrogen decreased tube formation in vitro. Expression of CD39 and phospho-ERK1/2 decreased in cardiac tissues from ovariectomized mice, whereas ENT1 expression increased with expected decreases in blood adenosine levels. Estradiol-induced upregulation of CD39 substantially increases adenosine availability, while augmenting vascular protective signaling responses. Control of CD39 by ERα follows on transcriptional regulation. These data suggest novel therapeutic avenues to explore in the amelioration of post-menopausal cardiovascular disease, by modulation of adenosinergic mechanisms. Full article

(This article belongs to the Special Issue Adenosine Metabolism-Key Targets in Cardiovascular Pharmacology)

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