Aerobic Exercise Ameliorates Myocardial Inflammation, Fibrosis and Apoptosis in High-Fat-Diet Rats by Inhibiting P2X7 Purinergic Receptors

Abstract

BackgroundHigh-fat-diet (HFD) is associated with chronic low-grade inflammation. P2X7 purinergic receptors (P2X7R) are key regulators of inflammasome activation. The benefits of exercise are partly attributed to its anti-inflammatory effect, but whether it regulates P2X7R expression to improve remodeling in cardiac myocytes treated by HFD is not completely clarified.MethodsThree groups of Sprague-Dawley (SD) rats were studied: (1) control group (fed a normal chow diet), (2) HFD group, and (3) HFD+ exercise group. H9c2 myocytes were pretreated with or without A438079 (a P2X7R inhibitor) and then exposed to 200 μM palmitic acid (PA) for 24 h. The levels of mRNA and protein were measured by real-time PCR and Western blot, respectively. Masson staining and hematoxylin-eosin (HE) staining were used to identify remodeling of the heart. The concentration of IL-1β in serum or supernatants were measured by ELISA.ResultsIn vivo, collagen deposition and the number of disordered cells significantly increased in the hearts of the HFD group compared to the control group. However, exercise markedly reversed these changes in the myocardium, and the same trends were observed in the expression of MMP9, collagen I and TGF-β. Notably, the expression of P2X7R, NLRP3, caspase-1 in the hearts, and serum IL-1β level were also greatly upregulated in the heart of the HFD diet rats, and all these changes were ameliorated in the HFD + EX group. As expected, exercise also reduced the number of TUNEL-positive cells, which was consistent with the caspase-3, Bax, and Bcl-2 results. Moreover, exercise reduced body weight and blood lipid concentrations in the HFD diet rats. In vitro, we observed that the hallmark of fibrosis, inflammation and apoptosis in H9c2 myocytes enhanced by PA, and the P2X7R inhibitor treatment significantly reduced the expression of the NLRP3, caspase-1, suppressed the secretion of IL-1β of H9c2 cells, inhibited collagen I, TGF-β, MMP9, Bax, caspase-3 levels and increased the expression of Bcl-2, compared with the PA group. In addition, a decrease of the number of TUNEL-positive cells used by A438079 further support that cardiomyocytes apoptosis could be inhibited.ConclusionAerobic exercise reversed the cardiac remodeling via the reduction of inflammation, fibrosis and apoptosis in HFD rats, at least in part through inhibiting P2X7R expression in cardiomyocytes.

Danegaptide Prevents TGFβ1-Induced Damage in Human Proximal Tubule Epithelial Cells of the Kidney

“…In contrast to gap junctions, which typically open under physiological conditions, undocked connexons, also termed hemichannels, have a low open probability and open in response to injury [ 10 ]. Altered hemichannel activity is associated with the pathophysiology of multiple disease states, with evidence linking altered cell-to-cell communication to increased senescence [ 54 ], inflammation [ 34 , 55 , 56 ] and fibrosis [ 18 , 19 , 20 , 21 ]. Data from our own lab demonstrate that the predominant connexin isoform in the proximal tubule (Cx43) is up-regulated in advanced CKD and correlates with elevated levels of TGFβ1 and severity of fibrosis and inflammation [ 24 ].…”

“…When unbound, connexons form hemichannels through which molecules, e.g., adenosine triphosphate (ATP), can be released into the local extracellular space to influence neighbouring cells via activation of purinoreceptors [ 11 ]. Expression of the purinergic P2X7 receptor (P2X7R) is upregulated in the renal tubules of individuals with diabetic kidney disease [ 12 ] and has been heavily implicated in the progression of fibrosis both in the kidney [ 13 , 14 , 15 , 16 , 17 ] and in other tissue types [ 18 , 19 , 20 , 21 ]. Unsurprisingly, targeting purinergic signalling has received considerable attention.…”

The P2X7 Receptor in Osteoarthritis

“…Regardless of the degree of fitness, acute exercise increased P2X7R expression and function. In another study, exercise reduced the expression levels of P2X7R, NLRP3, caspase-1, and IL-1β in plasma caused by a high-fat diet in Sprague Dawley rats, inhibiting inflammation and apoptosis, enhancing autophagy, and reducing myocardial damage ( Chen et al, 2019 ). It is thus evident that P2X7R plays an important role during exercise to relieve inflammation and other risk factors.…”

Collagen I Modifies Connexin-43 Hemichannel Activity via Integrin α2β1 Binding in TGFβ1-Evoked Renal Tubular Epithelial Cells

“…Hemichannels permit the release of small molecules (<1 kDa), e.g., adenosine triphosphate (ATP), into the local extracellular environment, where it can influence neighbouring cells via activation of purinoreceptors [ 12 ]. Expression of the purinergic P2X7 receptor (P2X7R) is upregulated in renal tubules of individuals with diabetic kidney disease [ 13 ], and has been heavily implicated in both progression of fibrosis in the kidney [ 14 , 15 , 16 , 17 ] and in other tissue types [ 18 , 19 , 20 , 21 ].…”