Platelet pannexin-1 channels modulate neutrophil activation and migration but not the progression of abdominal aortic aneurysm

Abstract

Abdominal aortic aneurysm (AAA) is a common disease and highly lethal if untreated. The progressive dilatation of the abdominal aorta is accompanied by degradation and remodeling of the vessel wall due to chronic inflammation. Pannexins represent anion-selective channels and play a crucial role in non-vesicular ATP release to amplify paracrine signaling in cells. Thus, pannexins are involved in many (patho-) physiological processes. Recently, Panx1 channels were identified to be significantly involved in abdominal aortic aneurysm formation through endothelial derived Panx1 regulated inflammation and aortic remodeling. In platelets, Panx1 becomes activated following activation of glycoprotein (GP) VI. Since platelets play a role in cardiovascular diseases including abdominal aortic aneurysm, we analyzed the contribution of platelet Panx1 in the progression of abdominal aortic aneurysm. We detected enhanced Panx1 plasma levels in abdominal aortic aneurysm patients. In experimental abdominal aortic aneurysm using the pancreatic porcine elastase (PPE) mouse model, a major contribution of platelet Panx1 channels in platelet activation, pro-coagulant activity of platelets and platelet-mediated inflammation has been detected. In detail, platelets are important for the migration of neutrophils into the aortic wall induced by direct cell interaction and by activation of endothelial cells. Decreased platelet activation and inflammation did not affect ECM remodeling or wall thickness in platelet-specific Panx1 knock-out mice following PPE surgery. Thus, aortic diameter expansion at different time points after elastase infusion of the aortic wall was unaltered in platelet-specific Panx1 deficient mice suggesting that the modulation of inflammation alone does not affect abdominal aortic aneurysm formation and progression. In conclusion, our data strongly supports the role of platelets in inflammatory responses in abdominal aortic aneurysm via Panx1 channels and adds important knowledge about the significance of platelets in abdominal aortic aneurysm pathology important for the establishment of an anti-platelet therapy for abdominal aortic aneurysm patients.

Pannexin 1 Channels Control Cardiomyocyte Metabolism and Neutrophil Recruitment During Non-Ischemic Heart Failure

“…Conversely, Panx1 MyHC6 do not have any significant increase, and the percent change from baseline in left ventricular volume at both these points is significantly less than their Panx1 fl/fl counterparts. With this in mind, we speculate that one immune cell recruitment, as has been shown in multiple mouse models 24,35,57 . Furthermore, modulating cardiomyocyte metabolism to increase glucose uptake may prevent an energy imbalance which is thought to be a driving factor in cardiac muscle function decline.…”

“…33,69,70 . However, it is is not completely 24,35,57 . Historically, treatment of heart failure in patients has focused on therapies which treat the symptoms of the disease, such as edema and dyspnea, rather than directly targeting cardiac function or preventing functional decline of the cardiac muscle.…”

“…Systemic PANX1 channel blockade may improve paYent outcomes by prevenYng immune cell recruitment, as has been shown in mulYple mouse models 24,35,57 . Furthermore, modulaYng cardiomyocyte metabolism to increase glucose uptake may prevent an energy imbalance which is thought to be a driving factor in the funcYonal decline of cardiac 24,35,57 . Furthermore, modulaDng cardiomyocyte metabolism to increase glucose uptake may prevent an energy imbalance which is thought to be a driving factor in cardiac muscle funcDon decline.…”

“…AddiWonally, we observed lower expression of Lamb1 (encoding Laminin subunit beta 1) and Lama5 (encoding laminin subunit alpha 5) as well as Vtn (encoding VitronecWn) suggesWve of decreased cell-cell adhesion and fibrosis (Figure 5C). Since PANX1 channel funcWon has been associated with acWvaWon of a variety of purinergic receptors 29,[52][53][54] , we examined the expression of purinergic signaling receptors and other associated molecular regulators in our RNA-Seq dataset (WikiPathway "Purinergic signaling"). We found lower expression of P2yr1, P2rx1, P2ry14, and Adora2a in hearts of Panx1 MyHC6 mice (Figure 5D) compared to Panx1 fl/fl controls.…”

Collagen receptor GPVI-mediated platelet activation and pro-coagulant activity aggravates inflammation and aortic wall remodelling in abdominal aortic aneurysm

“…Similary, in various preclinical animal models such as the angiotensin-II (Ang-II) and the pancreatic porcine elastase (PPE) infusion model, anti-platelet treatment or genetic ablation of specific platelet proteins have demonstrated a beneficial impact on AAA rupture rates, AAA growth and inflammation (12)(13)(14)(15)(16)(17)(18).…”