Connexins (Cx) are members of a protein family which enable extracellular and intercellular communication through hemichannels and gap junctions (GJ), respectively. Cx take part in transporting important cell–cell messengers such as 3′,5′-cyclic adenosine monophosphate (cAMP), adenosine triphosphate (ATP), and inositol 1,4,5-trisphosphate (IP3), among others. Therefore, they play a significant role in regulating cell homeostasis, proliferation, and differentiation. Alterations in Cx distribution, degradation, and post-translational modifications have been correlated with cancers, as well as cardiovascular and neurological diseases. Depending on the isoform, Cx have been shown either to promote or suppress the development of atherosclerosis, a progressive inflammatory disease affecting large and medium-sized arteries. Cx might contribute to the progression of the disease by enhancing endothelial dysfunction, monocyte recruitment, vascular smooth muscle cell (VSMC) activation, or by inhibiting VSMC autophagy. Inhibition or modulation of the expression of specific isoforms could suppress atherosclerotic plaque formation and diminish pro-inflammatory conditions. A better understanding of the complexity of atherosclerosis pathophysiology linked with Cx could result in developing novel therapeutic strategies. This review aims to present the role of Cx in the pathogenesis of atherosclerosis and discusses whether they can become novel therapeutic targets.

https://www.mdpi.com/1422-0067/24/3/2600/pdf?version=1675059563

The Potential Role of Connexins in the Pathogenesis of Atherosclerosis

The human immunodeficiency virus-1 (HIV) enters the brain shortly after infection, leading to long-term neurological complications in half of the HIV-infected population, even in the current anti-retroviral therapy (ART) era. Despite decades of research, no biomarkers can objectively measure and, more importantly, predict the onset of HIV-associated neurocognitive disorders. Several biomarkers have been proposed; however, most of them only reflect late events of neuronal damage. Our laboratory recently identified that ATP and PGE2, inflammatory molecules released through Pannexin-1 channels, are elevated in the serum of HIV-infected individuals compared to uninfected individuals and other inflammatory diseases. More importantly, high circulating ATP levels, but not PGE2, can predict a decline in cognition, suggesting that HIV-infected individuals have impaired ATP metabolism and associated signaling. We identified that Pannexin-1 channel opening contributes to the high serological ATP levels, and ATP in the circulation could be used as a biomarker of HIV-associated cognitive impairment. In addition, we believe that ATP is a major contributor to chronic inflammation in the HIV-infected population, even in the anti-retroviral era. Here, we discuss the mechanisms associated with Pannexin-1 channel opening within the circulation, as well as within the resident viral reservoirs, ATP dysregulation, and cognitive disease observed in the HIV-infected population.

/pdf/the-role-of-pannexin-1-channels-in-hiv-and-neurohiv-1wwqo788.pdf

The Role of Pannexin-1 Channels in HIV and NeuroHIV Pathogenesis

Anti-inflammation Nanomedicine Shots through Atherosclerotic Plaques for Targeted Treatment and Precise Diagnosis

The NLRP3-inflammasome is a cytosolic multiprotein complex that triggers an inflammatory response to certain danger signals. Recently adenosine diphosphate (ADP) was found to activate the NLRP3-inflammasome in murine macrophages via the P2Y1 receptor. Blockade of this signaling pathway reduced disease severity in a murine colitis-model. However, the role of the ADP/P2Y1-axis has not yet been studied in humans. This present study confirmed ADP-dependent NLRP3-inflammasome activation in murine macrophages, but found no evidence for a role of ADP in inflammasome activation in humans. We investigated the THP1 cell line as well as primary monocytes and further looked at macrophages. Although all cells express the three human ADP-receptors P2Y1, P2Y12 and P2Y13, independent of priming, neither increased ASC-speck formation could be detected with flow cytometry nor additional IL-1β release be found in the culture supernatant of ADP stimulated cells. We now show for the first time that the responsiveness of monocytes and macrophages to ADP as well as the regulation of its purinergic receptors is very much dependent on the species. Therefore the signaling pathway found to contribute to colitis in mice is likely not applicable to humans. 

https://link.springer.com/content/pdf/10.1007/s11302-023-09953-y.pdf

ADP as a novel stimulus for NLRP3-inflammasome activation in mice fails to translate to humans.

Purinergic P2X Receptors as Therapeutic Targets

Extracellular adenosine-5'-triphosphate (ATP) acts as an import signaling molecule mediating inflammation via purinergic P2 receptors. ATP binds to the purinergic receptor P2X4 and promotes inflammation via increased expression of pro-inflammatory cytokines. Because of the central role of inflammation, we assumed a functional contribution of the ATP-P2X4-axis in atherosclerosis. Expression of P2X4 was increased in atherosclerotic aortic arches from low-density lipoprotein receptor-deficient mice being fed a high cholesterol diet as assessed by real-time polymerase chain reaction and immunohistochemistry. To investigate the functional role of P2X4 in atherosclerosis, P2X4-deficient mice were crossed with low-density lipoprotein receptor-deficient mice and fed high cholesterol diet. After 16 weeks, P2X4-deficient mice developed smaller atherosclerotic lesions compared to P2X4-competent mice. Furthermore, intravital microscopy showed reduced ATP-induced leukocyte rolling at the vessel wall in P2X4-deficient mice. Mechanistically, we found a reduced RNA expression of CC chemokine ligand 2 (CCL-2), C-X-C motif chemokine-1 (CXCL-1), C-X-C motif chemokine-2 (CXCL-2), Interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) as well as a decreased nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-inflammasome priming in atherosclerotic plaques from P2X4-deficient mice. Moreover, bone marrow derived macrophages isolated from P2X4-deficient mice revealed a reduced ATP-mediated release of CCL-2, CC chemokine ligand 5 (CCL-5), Interleukin-1β (IL-1β) and IL-6. Additionally, P2X4-deficient mice shared a lower proportion of pro-inflammatory Ly6Chigh monocytes and a higher proportion of anti-inflammatory Ly6Clow monocytes, and expressend less endothelial VCAM-1. Finally, increased P2X4 expression in human atherosclerotic lesions from carotid endarterectomy was found, indicating the importance of potential implementations of this study's findings for human atherosclerosis. Collectively, P2X4 deficiency reduced experimental atherosclerosis, plaque inflammation and inflammasome priming, pointing to P2X4 as a potential therapeutic target in the fight against atherosclerosis. 

https://www.nature.com/articles/s41598-022-06706-6.pdf

P2X4 deficiency reduces atherosclerosis and plaque inflammation in mice

\n \n \n Metabolic syndrome clusters the main risk factors for cardiovascular diseases and endocrine dysfunction. Novel studies show that the important underlying mechanism is a long term inflammation of adipose tissue with a gradual shift from the anti-inflammatory M2 towards the pro-inflammatory M1 macrophages (pathognomonic). Massive hypertrophy induces adipocyte death, which releases DAMPs like nucleotides recognized by purinergic receptors orchestrating ongoing inflammatory process. Interestingly, we found Gi coupled P2Y13R only expressed on M1 macrophages, not in M0 (unstimulated) and M2 macrophages.\n Nevertheless, the role of P2Y13R in the immune system and especially macrophages is currently unknown. Given its pivotal role in central metabolic processes (P2Y13R has been described in insulin secretory signalling) together with its unique expression in its pathognomonic inflammatory macrophage subtype makes it an interesting candidate to investigate its role in metabolic syndrome.\n \n \n \n Due to the unique expression of P2Y13R on M1 macrophages we hypothesise an improved outcome in a high-fat diet induced metabolic syndrome by interfering with the P2Y13 signalling cascade.\n \n \n \n BMDM differentiation to macrophages using M-CSF and subsequent stimulation with medium (M0), LPS and IFNγ (M1) or IL4 (M2); Expression of P2Rs quantified using Taqman qPCR.\n Male C57Bl6/J wild-type (WT) and P2Y13-deficient (KO) mice were fed with a high-fat diet (HFD) for 20 weeks; On week 15 we performed the ITT, on week 16 the GTT. Metabolic performance was monitored by metabolic caging.\n \n \n \n We observed a unique expression of P2Y13R on M1 macrophages. Adult P2Y13-deficient mice showed a higher O2 consumption compared to adult C57Bl6/J wild-type mice (AUC of O2 consumption 2nd day= KO: 61620±2261mL/kg vs WT: 53830±916.1mL/kg, p=0.0331). Although both P2Y13−/− mice and WT littermates consumed comparable amount of food (daily food intake per mouse → KO: 3.97±0.25g vs WT: 3.76±0.18g), P2Y13 deficient animals showed significantly decelerated weight gain (e.g. on week 15 → KO: 142±2% (n=10) vs WT: 198±5% (n=10), p<0.0001). Obese P2Y13−/− animals outperformed obese WT littermates in a peritoneal glucose tolerance test (2h after glucose injection → KO: 272.9±21.0 mg/dL (n=10) vs WT: 532.6±21.2 (n=10) mg/dL, p<0.0001). There was no difference in the cell amount of stromal vascular fraction cells.\n \n \n \n Global P2Y13 deficiency leads to an improved outcome in metabolic syndrome with an increased protection against developing an insulin resistance as shown through an improved glucose tolerance and basal glucose levels, a decelerated weight gain despite comparable food consumption and a better metabolic turnover. Observing these beneficial metabolic improvements, we hypothesise that antagonization of P2Y13R could be a promising therapeutic target in the field of metabolic syndrome.\n

http://academic.oup.com/eurheartj/article-pdf/40/Supplement_1/ehz746.0070/30202828/ehz746.0070.pdf

5221Knockout of purinergic receptor Y13 (P2Y13) results in an improved outcome in metabolic syndrome in mice

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P2X4 deficiency reduces atherosclerosis and plaque inflammation in mice

5221Knockout of purinergic receptor Y13 (P2Y13) results in an improved outcome in metabolic syndrome in mice