Glycolysis Inhibition Alleviates Cardiac Fibrosis After Myocardial Infarction by Suppressing Cardiac Fibroblast Activation

Abstract

Objective: To explore the role of glycolysis in cardiac fibroblast (CF) activation and cardiac fibrosis after myocardial infarction (MI).Method:In vivo: 2-Deoxy-D-glucose (2-DG), a glycolysis inhibitor, was injected into the abdominal cavity of the MI or sham mice every day. On the 28th day, cardiac function was measured by ultrasonic cardiography, and the hearts were harvested. Masson staining and immunofluorescence (IF) were used to evaluate the fibrosis area, and western blot was used to identify the glycolytic level. In vitro, we isolated the CF from the sham, MI and MI with 2-DG treatment mice, and we also activated normal CF with transforming growth factor-β1 (TGF-β1) and block glycolysis with 2-DG. We then detected the glycolytic proteins, fibrotic proteins, and the concentrations of lactate and glucose in the culture medium. At last, we further detected the fibrotic and glycolytic markers in human fibrotic and non-fibrotic heart tissues with masson staining, IF and western blot.Result: More collagen and glycolytic protein expressions were observed in the MI mice hearts. The mortality increased when mice were treated with 2-DG (100 mg/kg/d) after the MI surgery (Log-rank test, P < 0.05). When the dosage of 2-DG declined to 50 mg/kg/d, and the treatment was started on the 4th day after MI, no statistical difference of mortality between the two groups was observed (Log-rank test, P = 0.98). The collagen volume fraction was smaller and the fluorescence signal of α-smooth muscle actin (α-SMA) was weaker in mice treated with 2-DG than PBS. In vitro, 2-DG could significantly inhibit the increased expression of both the glycolytic and fibrotic proteins in the activated CF.Conclusion: Cardiac fibrosis is along with the enhancement of CF activation and glycolysis. Glycolysis inhibition can alleviate cardiac fibroblast activation and cardiac fibrosis after myocardial infarction.

Emerging Roles of SIRT3 in Cardiac Metabolism

“…Interestingly, SIRT3-KO mice show increased fibrosis in several organs including the heart, lung, liver and kidney (62). Enhanced glucose metabolism, particularly glycolysis is essential for cardiac fibroblast activation and cardiac fibrosis (133,134). Consistent with this, limiting glycolysis in heart has been shown to decrease cardiac fibrosis post myocardial infarction (134).…”

“…Enhanced glucose metabolism, particularly glycolysis is essential for cardiac fibroblast activation and cardiac fibrosis (133,134). Consistent with this, limiting glycolysis in heart has been shown to decrease cardiac fibrosis post myocardial infarction (134). The protective role of SIRT3 against kidney fibrosis under diabetic conditions is known to be mediated by suppression of HIF-1α and PKM2 dimer formation that upregulates expression of key glycolytic enzymes (135)(136)(137).…”

Gpx3 and Egr1 Are Involved in Regulating the Differentiation Fate of Cardiac Fibroblasts under Pressure Overload

“…Many studies have reported that excessive glycolysis is involved in the process of organ fibrosis. Thus, inhibition of glycolysis can inhibit the activation of fibroblasts and improve organ fibrosis [55][56][57][58]. This change of energy metabolism may be an adaptive measure under hypoxia, as cells tend to undergo glycolysis in the absence of oxygen [59,60].…”

Excessive Sodium Intake Leads to Cardiovascular Disease by Promoting Sex-Specific Dysfunction of Murine Heart

“…Masson staining of murine hearts was performed according to a previously published study (27). All cardiac sections from CONMH, MH8W, CONFH, and FH8W groups were placed in xylene I-III (10023418, Sinopharm Chemical Reagent Co., Ltd., Shanghai, China) for 15-20 min and then rinsed with 75-100% ethanol (100092683, Sinopharm Chemical Reagent Co., Ltd., Shanghai, China) for 5 min and rinsed with distilled water.…”