Adenosine A3 receptor-induced proliferation of primary human coronary smooth muscle cells involving the induction of early growth response genes

Hinze, Annette Viktoria; Mayer, Péter; Harst, Anja; Kügelgen, Ivar von

doi:10.1016/j.yjmcc.2012.08.003

Cited by 14 publications

(14 citation statements)

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“…The maintenance of expression and function of P2X 1 receptors in our experimental system may be due to the culture conditions used and correlates with the continuous expression of smooth muscle α-actin in these cultured cells [25]. There is the possibility that P2X analogs, which are ATP derivates, become degraded to adenosine via 5′-nucleotidases located on the surface of the cells.…”

Section: Discussionmentioning

confidence: 94%

“…Genetically induced overexpression of NR4A1 and drug-induced induction of NR4A1 are known to inhibit proliferation of both arterial and venous smooth muscle cells [21][22][23][24]. In contrast to the effects mediated by adenosine A 2B receptors, activation of adenosine A 3 receptors by the selective agonist 2-chloro-IB-MECA increased the proliferation of cultured human coronary smooth muscle cells [25]. 2-chloro-IB-MECA did not change the expression of NR4A1, but increased the expression of the transcription factors early growth response protein (EGR)-2 and EGR-3 [25].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, coronary smooth muscle cells and myocardial cells are likely to be derived from a common precursor cell [32], suggesting potential differences of coronary smooth muscle on the one hand and noncoronary vascular smooth muscle on the other hand. Therefore, we now examined the effects of α,β-methylene-ATP and its analog β,γ-methylene-ATP on the proliferation of human coronary smooth muscle cells cultured under conditions suitable to maintain the contractile smooth muscle phenotype [20,25]. In contrast to α,β-methylene-ATP, β,γ-methylene-ATP has been shown to exert mitogenic effects in rat vascular smooth muscle cells [11,29].…”

Section: Introductionmentioning

confidence: 99%

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P2X1 receptor-mediated inhibition of the proliferation of human coronary smooth muscle cells involving the transcription factor NR4A1

Hinze

Mayer

Harst

et al. 2013

Purinergic Signalling

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Adenine nucleotides acting at P2X 1 receptors are potent vasoconstrictors. Recently, we demonstrated that activation of adenosine A 2B receptors on human coronary smooth muscle cells inhibits cell proliferation by the induction of the nuclear receptor subfamily 4, group A, member 1 (NR4A1; alternative notation Nur77). In the present study, we searched for long-term effects mediated by P2X 1 receptors by analyzing receptor-mediated changes in cell proliferation and in the expression of NR4A1. Cultured human coronary smooth muscle cells were treated with selective receptor ligands. Effects on proliferation were determined by counting cells and measuring changes in impedance. The induction of transcription factors was assessed by qPCR. The P2X receptor agonist α,β-methylene-ATP and its analog β,γ-methylene-ATP inhibited cell proliferation by about 50 % after 5 days in culture with half-maximal concentrations of 0.3 and 0.08 μM, respectively. The effects were abolished or markedly attenuated by the P2X 1 receptor antagonist NF449 (carbonylbis-imino-benzenetriylbis-(carbonylimino)tetrakis-benzene-1,3-disulfonic acid; 100 nM and 1 μM). α,β-methylene-ATP and β,γ-methylene-ATP applied for 30 min to 4 h increased the expression of NR4A1; NF449 blocked or attenuated this effect. Small interfering RNA directed against NR4A1 diminished the antiproliferative effects of α,β-methylene-ATP and β,γ-methylene-ATP. α,β-methylene-ATP (0.1 to 30 μM) decreased migration of cultured human coronary smooth muscle cells in a chamber measuring changes in impedance; NF449 blocked the effect. In conclusion, our results demonstrate for the first time that adenine nucleotides acting at P2X 1 receptors inhibit the proliferation of human coronary smooth muscle cells via the induction of the early gene NR4A1.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

P2X1 receptor-mediated inhibition of the proliferation of human coronary smooth muscle cells involving the transcription factor NR4A1

Hinze

Mayer

Harst

et al. 2013

Purinergic Signalling

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“…High A 3 AR expression has been revealed in the human coronary and carotid artery (Hinze et al, 2012;Grandoch et al, 2013).…”

Section: Distribution Of the A 3 Adenosine Receptormentioning

confidence: 99%

The A₃Adenosine Receptor: History and Perspectives

et al. 2014

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“…Importantly, while no direct evidence has been found for the existence of the A 3 receptor in cardiomyocytes, several studies have demonstrated A 3 receptor-mediated cardioprotection from ischaemic injury (Tracey et al, 1997; Thourani et al, 1999aThourani et al, , 1999bCross et al, 2002;Harrison et al, 2002;Headrick and Peart, 2005) and doxorubicininduced cardiotoxicity (Shneyvays et al, 1998;Shneyvays et al, 2001). Additionally, high A 3 receptor expression has been documented in the human coronary and carotid arteries (Hinze et al, 2012;Grandoch et al, 2013).…”

Section: Adenosine Receptorsmentioning

confidence: 99%

Identification of A₃ adenosine receptor agonists as novel non‐narcotic analgesics

Janes

Symons-Liguori

Jacobson

et al. 2016

British J Pharmacology

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Chronic pain negatively impacts the quality of life in a variety of patient populations. The current therapeutic repertoire is inadequate in managing patient pain and warrants the development of new therapeutics. Adenosine and its four cognate receptors (A 1 , A 2A , A 2B and A 3 ) have important roles in physiological and pathophysiological states, including chronic pain. Preclinical and clinical studies have revealed that while adenosine and agonists of the A 1 and A 2A receptors have antinociceptive properties, their therapeutic utility is limited by adverse cardiovascular side effects. In contrast, our understanding of the A 3 receptor is only in its infancy, but exciting preclinical observations of A 3 receptor antinociception, which have been bolstered by clinical trials of A 3 receptor agonists in other disease states, suggest pain relief without cardiovascular side effects and with sufficient tolerability. Our goal herein is to briefly discuss adenosine and its receptors in the context of pathological pain and to consider the current data regarding A 3 receptor-mediated antinociception. We will highlight recent findings regarding the impact of the A 3 receptor on pain pathways and examine the current state of selective A 3 receptor agonists used for these studies. The adenosine-to-A 3 receptor pathway represents an important endogenous system that can be targeted to provide safe, effective pain relief from chronic pain. AbbreviationsADA, adenosine deaminase; ADK, adenosine kinase; CCI, chronic constriction injury; CIPN, chemotherapy-induced peripheral neuropathy; CPP, conditioned place preference; ENT, equilibrative nucleoside transporter; PN, peroxynitrite; RVM, rostral ventromedial medulla; SO, superoxide; TLR4, toll-like receptor 4 BJP IntroductionChronic pain afflicts an estimated 10% of the world's adult population (Goldberg and McGee, 2011). The current therapeutic approaches for chronic pain include but are not limited to the use of nonsteroidal anti-inflammatory drugs (NSAIDs), antidepressants, anticonvulsants and opioid pain relievers; however, these strategies are frequently either inadequate or are associated with side effects that reduce quality of life or result in the discontinuation of therapy (Goldberg and McGee, 2011;Pizzo and Clark, 2012). The search for new therapeutic targets is therefore of great importance. Adenosine and two of its associated adenosine receptor subtypes, the A 1 and the A 2A receptor, have been investigated in the field of pain with varying degrees of success; however, these agents lack a useful therapeutic index due to cardiovascular side effects. In response, the focus of research has turned to the previously overlooked A 3 receptor, which displays both preclinical antinociceptive properties (Yoon et al., 2004;Janes et al., 2014bJanes et al., , 2015Ford et al., 2015;Little et al., 2015) and, in trials for non-pain conditions including psoriasis, hepatitis, rheumatoid arthritis, and glaucoma, offers a therapeutic index and tolerability that would be suitable for ...

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Adenosine A3 receptor-induced proliferation of primary human coronary smooth muscle cells involving the induction of early growth response genes

Cited by 14 publications

References 38 publications

P2X1 receptor-mediated inhibition of the proliferation of human coronary smooth muscle cells involving the transcription factor NR4A1

P2X1 receptor-mediated inhibition of the proliferation of human coronary smooth muscle cells involving the transcription factor NR4A1

The A₃Adenosine Receptor: History and Perspectives

Identification of A₃ adenosine receptor agonists as novel non‐narcotic analgesics

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Adenosine A3 receptor-induced proliferation of primary human coronary smooth muscle cells involving the induction of early growth response genes

Cited by 14 publications

References 38 publications

P2X1 receptor-mediated inhibition of the proliferation of human coronary smooth muscle cells involving the transcription factor NR4A1

P2X1 receptor-mediated inhibition of the proliferation of human coronary smooth muscle cells involving the transcription factor NR4A1

The A3Adenosine Receptor: History and Perspectives

Identification of A3 adenosine receptor agonists as novel non‐narcotic analgesics

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Product

Resources

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The A₃Adenosine Receptor: History and Perspectives

Identification of A₃ adenosine receptor agonists as novel non‐narcotic analgesics