Aerobic Exercise Inhibited P2X7 Purinergic Receptors to Improve Cardiac Remodeling in Mice With Type 2 Diabetes

Abstract

Background: Diabetic cardiomyopathy (DCM), the main complication of diabetes mellitus, presents as cardiac dysfunction by ventricular remodeling. In addition, the inhibition of P2X7 purinergic receptors (P2X7R) alleviates cardiac fibrosis and apoptosis in Type 1 diabetes. However, whether exercise training improves cardiac remodeling by regulating P2X7R remains unknown.Methods: Db/db mice spontaneously induced with type 2 diabetes and high-fat diet (HFD) and mice with streptozotocin (STZ)-induced type 2 diabetes mice were treated by 12-week treadmill training. Cardiac functions were observed by two-dimensional echocardiography. Hematoxylin-eosin staining, Sirius red staining and transmission electron microscopy were respectively used to detect cardiac morphology, fibrosis and mitochondria. In addition, real-time polymerase chain reaction and Western Blot were used to detect mRNA and protein levels.Results: Studying the hearts of db/db mice and STZ-induced mice, we found that collagen deposition and the number of disordered cells significantly increased compared with the control group. However, exercise markedly reversed these changes, and the same tendency was observed in the expression of MMP9, COL-I, and TGF-β, which indicated cardiac fibrotic and hypertrophic markers, including ANP and MyHC expression. In addition, the increased Caspase-3 level and the ratio of Bax/Bcl2 were reduced by exercise training, and similar results were observed in the TUNEL test. Notably, the expression of P2X7R was greatly upregulated in the hearts of db/db mice and HFD + STZ-induced DM mice and downregulated by aerobic exercise. Moreover, we indicated that P2X7R knock out significantly reduced the collagen deposition and disordered cells in the DM group. Furthermore, the apoptosis levels and TUNEL analysis were greatly inhibited by exercise or in the P2X7R−/− group in DM. We found significant differences between the P2X7R−/− + DM + EX group and DM + EX group in myocardial tissue apoptosis and fibrosis, in which the former is significantly milder. Moreover, compared with the P2X7R−/− + DM group, the P2X7R−/− + DM + EX group represented a lower level of cardiac fibrosis. The expression levels of TGF-β at the protein level and TGF-β and ANP at the genetic level were evidently decreased in the P2X7R−/− + DM + EX group.Conclusion: Aerobic exercise reversed cardiac remodeling in diabetic mice at least partly through inhibiting P2X7R expression in cardiomyocytes.

Moderate- and High-Intensity Endurance Training Alleviate Diabetes-Induced Cardiac Dysfunction in Rats

“…Besides improving diastolic dysfunction, MIT also normalized systolic function by significantly increasing EF and FS in the WD-fed rats. In line with our findings, an increased EF and FS were observed following 8 weeks and 12 weeks of MIT in HFD and STZ-induced rats and mice, respectively [ 84 , 85 ]. Furthermore, 8 weeks of HIIT has been demonstrated to only improve diastolic function (i.e., the ratio of peak mitral flow velocity versus peak mitral annular velocity (e/e’)), whereas systolic function (i.e., FS and EF) remained unchanged in HFD-induced diabetic mice [ 72 ].…”

“…Three studies have previously indicated that HIIT potentially induced physiological cardiac hypertrophy or a so-called athlete’s heart, assessed as increased heart weight and size and improved cardiac function, in HFD-induced T2DM mice [ 72 , 78 , 83 ]. Additionally, three studies on HFD-induced T2DM mice reported no changes in heart weight [ 77 ] or PWT [ 84 , 85 ] following MIT, suggesting the absence of physiological hypertrophic effects. Here, we are the first to show a decreased heart weight and PWT following both MIT and HIIT in high-sucrose diet-induced diabetic cardiomyopathy, potentially indicating the therapeutic nature of endurance exercise training against pathological cardiac hypertrophy.…”

“…These findings are in line with results reported by other studies, with some reporting attenuated cardiac fibrosis following 8 to 10 weeks of MIT but not HIIT in HFD-fed mice [ 78 , 97 ], while others confirming a reduced myocardial collagen content, assessed as hydroxyproline levels, after 10 weeks of HIIT [ 72 ]. Furthermore, mRNA expression of matrix metalloproteinase 2, an enzyme involved in cardiac extracellular matrix (ECM) degradation, has previously been shown to be decreased after both exercise training modalities [ 78 , 84 , 85 ]. Here, the exercise-induced decrease in fibrosis was accompanied by, even if not significant, clear lower protein levels of LOX following MIT.…”

Angiotension II directly bind P2X7 receptor to induce myocardial ferroptosis and remodeling by activating human antigen R

“…The amount of collagen deposition was determined by Masson's trichrome (G1340, Solarbio, China) or Sirius Red staining (G1472, Solarbio, China). An anti-4-hydroxynonenal antibody (MAB3249, R&D Systems) was used for immunohistochemical staining of heart sections according to our previously described procedures [ 20 ]. The pathological sections were imaged using an upright microscope (400 × magnification; Leica, Germany) and subsequently subjected to histopathological evaluation.…”

NLRP3 inflammasome and pyroptosis in cardiovascular diseases and exercise intervention

“…In addition, recent studies in DCM mice have demonstrated that although exercise has a limited impact on interstitial fibrosis, it can effectively reverse cardiac dysfunction by reducing the activity of NLRP3 inflammasome and inhibiting pyroptosis (Takahashi, 2019;Zhang et al, 2019). Moreover, in DCM rat models, elevated expression levels of the P2X7 receptor, NLRP3, caspase-1, and serum IL-1β were observed in the myocardium (Wang et al, 2022). However, following a 12-week treadmill running regimen in these rats, improvements were observed in terms of collagen deposition, cell disorder, as well as the expression levels of NLRP3, caspase-1, P2X7 receptor, and IL-1β within their heart (Zhang et al, 2015).…”