SIRT3/AMPK Signaling Pathway Regulates Lipid Metabolism and Improves Vulnerability to Atrial Fibrillation in Dahl Salt-Sensitive Rats

Abstract

Abstract BACKGROUND Hypertension may result in atrial fibrillation (AF) and lipid metabolism disorders. The Sirtuins3 (SIRT3)/AMP-activated protein kinase (AMPK) signaling pathway has the capacity to regulate lipid metabolism disorders and the onset of AF. We hypothesize that the SIRT3/AMPK signaling pathway suppresses lipid metabolism disorders, thereby mitigating salt-sensitive hypertension (SSHT)-induced susceptibility to AF. METHODS The study involved 7-week-old male Dahl salt-sensitive that were fed either a high-salt diet (8% NaCl; DSH group) or a normal diet (0.3% NaCl; DSN group). Then DSH group was administered either oral metformin (MET, an AMPK agonist) or intraperitoneal injection of Honokiol (HK, a SIRT3 agonist). This experimental model allowed for the measurement of Systolic blood pressure (SBP), the expression levels of lipid metabolism-related biomarkers, pathological examination of atrial fibrosis, and lipid accumulation, as well as AF inducibility and AF duration. RESULTS DSH decrease SIRT3, phosphorylation-AMPK, and very long-chain acyl-CoA dehydrogenase, (VLCAD) expression, increased FASN and FABP4 expression and concentrations of free fatty acid and triglyceride, atrial fibrosis and lipid accumulation in atrial tissue, enhanced level of SBP, promoted AF induction rate and prolonged AF duration, which are blocked by MET and HK. Our results also showed that the degree of atrial fibrosis was negatively correlated with VLCAD expression, but positively correlated with the expression of FASN and FABP4. CONCLUSIONS We have confirmed that a high-salt diet can result in hypertension, and associated atrial tissue lipid metabolism dysfunction. This condition is linked to the inhibition of the SIRT3/AMPK signaling pathway, which plays a significant role in the progression of susceptibility to AF in SSHT rats.