P2Y Purinergic Receptors, Endothelial Dysfunction, and Cardiovascular Diseases

Strassheim, Derek; Verin, Alexander D.; Bátori, Róbert; Nijmeh, Hala; Burns, Nana; Kovács‐Kása, Anita; Umapathy, Nagavedi S.; Kotamarthi, Janavi; Gokhale, Yash; Karoor, Vijaya; Stenmark, Kurt R.; Gerasimovskaya, Evgenia

doi:10.3390/ijms21186855

Cited by 25 publications

(24 citation statements)

References 147 publications

(211 reference statements)

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“…P2 receptors are composed of P2XRs, the ligand-gated cation channels, and the P2YR subtypes are stimulated by different endogenous nucleotides [ 442 ]. The different receptors are coupled to either Gq to activate PKC, Gs to activate cAMP, and Gi to inhibit cAMP [ 479 , 480 , 481 ]. Purinergic receptors P 2 Y 1 R, P 2 Y 2 R or P 2 Y 4 R, and P 2 Y 11 R promote adipogenic differentiation of stem cells derived from bone marrow or adipose tissue [ 447 ].…”

Section: Nucleotide-nucleoside Metabolitesmentioning

confidence: 99%

“…These results suggest that age-dependent increases in P2Y 6 R expression determine Ang II’s pathological vascular effects and cardiovascular risk. P 2 Y 6 R-deficient mice exhibit a decrease in Ang II-induced pathological arterial remodeling in response to hypertension than wild-type mice [ 503 ] P 2 Y 1 R and P 2 Y 13 R are expressed in pulmonary artery vasa vasorum endothelial cells and functionally involved in intracellular and mitochondrial Ca 2+ regulation associated with pathologic angiogenic expansion of the vasa vasorum network [ 479 , 505 ].…”

Section: Nucleotide-nucleoside Metabolitesmentioning

confidence: 99%

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Metabolite G-Protein Coupled Receptors in Cardio-Metabolic Diseases

Strassheim

Sullivan

Irwin

et al. 2021

Cells

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G protein-coupled receptors (GPCRs) have originally been described as a family of receptors activated by hormones, neurotransmitters, and other mediators. However, in recent years GPCRs have shown to bind endogenous metabolites, which serve functions other than as signaling mediators. These receptors respond to fatty acids, mono- and disaccharides, amino acids, or various intermediates and products of metabolism, including ketone bodies, lactate, succinate, or bile acids. Given that many of these metabolic processes are dysregulated under pathological conditions, including diabetes, dyslipidemia, and obesity, receptors of endogenous metabolites have also been recognized as potential drug targets to prevent and/or treat metabolic and cardiovascular diseases. This review describes G protein-coupled receptors activated by endogenous metabolites and summarizes their physiological, pathophysiological, and potential pharmacological roles.

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Section: Nucleotide-nucleoside Metabolitesmentioning

confidence: 99%

Section: Nucleotide-nucleoside Metabolitesmentioning

confidence: 99%

Metabolite G-Protein Coupled Receptors in Cardio-Metabolic Diseases

Strassheim

Sullivan

Irwin

et al. 2021

Cells

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“…[65][66][67] However, related to the current discourse is the role of purinergic sensing in PH, which has seen a relative explosion in interest within the past several years. 68 Genomewide RNA studies have previously demonstrated alteration in the purinergic G-protein coupled receptor P2Y-family in patients with PAH and secondary PH, compared to healthy controls. 69 Mechanistically, blocking P2Y 1 and P2Y 12 receptors blocks adenosine diphosphate (ADP)-induced pulmonary vasoconstriction in pigs.…”

Section: Molecular Mechanismsmentioning

confidence: 99%

The Third Man: DNA sensing as espionage in pulmonary vascular health and disease

et al. 2021

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For as long as nucleic acids have been utilized to vertically and horizontally transfer genetic ma-terial, living organisms have had to develop methods of recognizing cytosolic DNA as either pathogenic (microbial invasion) or physiologic (mitosis and cellular proliferation). Derangement in key signaling molecules involved in these pathways of nucleotide sensing result in a family of diseases labeled interferonopathies. An interferonopathy, characterized by constitutive expres-sion of type I interferons, ultimately manifests as severe autoimmune disease at a young age. Afflicted patients present with a constellation of immune-mediated conditions, including primary lung manifestations such as pulmonary fibrosis and pulmonary hypertension. The latter condi-tion is especially interesting in light of the known role that DNA damage plays in a variety of types of inherited and induced pulmonary hypertension, with free DNA detection elevated in the circula-tion of affected individuals. While little is known regarding the role of cytosolic DNA sensing in development of pulmonary vascular disease, exciting new research in the related fields of immu-nology and oncology potentially sheds light on future areas of fruitful exploration. As such, the goal of this review is to summarize the state of the field of nucleic acid sensing, extrapolating common shared pathways that parallel our knowledge of pulmonary hypertension, in a molecular and cell-specific manner. Principles of DNA sensing related to known pulmonary injury inducing stimuli are also evaluated, in addition to potential therapeutic targets. Finally, future directions in pulmonary hypertension research and treatments will be briefly discussed.

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“…There is experimental evidence supporting an important role of P2Y receptors in vasa vasorum neovascularization and pathologic vascular remodeling in PH [ 178 ]. Furthermore, in plexiform lesions from PAH patients, expression of CD39/ENTPD1, the ectonucleotidase responsible for the conversion of the nucleotides ATP and ADP to AMP, was decreased, suggesting that increased extracellular ATP level in the pulmonary vascular endothelium and within the angiomatoid proliferative lesions might contribute to excessive endothelial proliferation [ 44 ].…”

Section: Physiological Function and Dysfunction Of P2y2mentioning

confidence: 99%

Role of the Purinergic P2Y2 Receptor in Pulmonary Hypertension

Shihan

Novoyatleva

Lehmeyer

et al. 2021

IJERPH

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Pulmonary arterial hypertension (PAH), group 1 pulmonary hypertension (PH), is a fatal disease that is characterized by vasoconstriction, increased pressure in the pulmonary arteries, and right heart failure. PAH can be described by abnormal vascular remodeling, hyperproliferation in the vasculature, endothelial cell dysfunction, and vascular tone dysregulation. The disease pathomechanisms, however, are as yet not fully understood at the molecular level. Purinergic receptors P2Y within the G-protein-coupled receptor family play a major role in fluid shear stress transduction, proliferation, migration, and vascular tone regulation in systemic circulation, but less is known about their contribution in PAH. Hence, studies that focus on purinergic signaling are of great importance for the identification of new therapeutic targets in PAH. Interestingly, the role of P2Y2 receptors has not yet been sufficiently studied in PAH, whereas the relevance of other P2Ys as drug targets for PAH was shown using specific agonists or antagonists. In this review, we will shed light on P2Y receptors and focus more on the P2Y2 receptor as a potential novel player in PAH and as a new therapeutic target for disease management.

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P2Y Purinergic Receptors, Endothelial Dysfunction, and Cardiovascular Diseases

Cited by 25 publications

References 147 publications

Metabolite G-Protein Coupled Receptors in Cardio-Metabolic Diseases

Metabolite G-Protein Coupled Receptors in Cardio-Metabolic Diseases

The Third Man: DNA sensing as espionage in pulmonary vascular health and disease

Role of the Purinergic P2Y2 Receptor in Pulmonary Hypertension

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