Role of the MAPKs/TGF-β1/TRAF6 signaling pathway in postoperative atrial fibrillation

Abstract

ObjectivesTo explore the relationship between the MAPKs/TGF-β1/TRAF6 signaling pathway and atrial fibrosis in patients with rheumatic heart disease (RHD) and its role in atrial fibrillation (AF) after cardiac surgery on the basis of our previous animal study of the MAPKs/TGF-β1/TRAF6 signaling pathway in atrial fibrosis.MethodsA total of 57 patients with RHD without a history of AF consented to left atrial biopsy. Histopathology quantified the percentage of fibrosis, and real-time PCR and western blot assessed the mRNA and protein expression of TGF-β1, TRAF6, and connective tissue growth factor (CTGF), respectively. Western blot was also used to measure the protein expression of phosphorylated MAPKs and TGF-β-activated kinase 1 (TAK1). Serum angiotensin II (Ang II) levels were assayed using enzyme-linked immunosorbent assay (ELISA).ResultsEighteen patients developed AF, whereas 39 remained in sinus rhythm (SR). The severity of atrial fibrosis was significantly higher in patients who developed AF versus those who remained in SR; the mRNA and protein expression of TGF-β1, TRAF6 and CTGF were significantly higher in patients with AF. The protein expression of phosphorylated MAPKs and TAK1 was significantly increased in patients who developed AF compared with the patients who remained in SR. Serum Ang II levels were significantly higher in patients who developed AF versus those who remained in SR.ConclusionThe MAPKs/TGF-β1/TRAF6 signaling pathway is involved in atrial fibrosis in patients with RHD, which results in the occurrence of AF after cardiac surgery.

Atrial fibrosis underlying atrial fibrillation (Review)

“…Smad7, an inhibitory Smad, antagonizes the TGF-β/Smad signalling pathway (44). Non-canonical pathways include the mitogen-activated protein kinases (MAPKs)/TGF-β 1 /tumour necrosis factor (TNF) receptor associated factor 6/TGF-β-activated kinase 1, TGF-β 1 /cluster of differentiation (CD)44/signal transducer and activator of transcription 3 (STAT3) and angiotensin II (Ang II)/TGF-β/Ras homolog family member A (RhoA)/Rho-kinase (ROCK) signalling pathways (45)(46)(47). The thrombospondin-1/TGF-β/MMP-9 axis is also involved in atrial fibrosis in patients with AF (48).…”

The Role of the Mammalian Target of Rapamycin (mTOR) in Pulmonary Fibrosis

“…Within normal tissue such as lung, Smad signaling can stimulate fibroblast proliferation and collagen deposition, creating a hypoxic environment, which may further increase mTOR signaling to encourage cell survival and fibrosis [ 46 ]. Smad-independent TGF-β signaling pathways also operate by several other mediators involved in inflammation and proliferation, including TGF-β-associated kinase 1 (TAK1), extracellular signal-regulated kinase (ERK), mitogen activated protein kinase (MAPK), AKT, and JNK, [ 46 , 170 , 171 , 172 , 173 , 174 ]. TGF-β-mediated AKT signaling, downstream of PI3K may further activate mTOR signaling.…”

“…Importantly, TAK1 controls downstream p38 MAPK signaling, which promotes cardiac hypertrophy and atrial fibrosis [ 174 , 175 ]. Recent studies have highlighted the role of tumor necrosis factor receptor-associated factor (TRAF) family in pathological cardiac remodeling [ 173 , 174 , 175 , 176 , 177 , 178 ]. TRAF6, in particular, is a critical activator of TAK1 and has been highlighted as a potential target in cardiac hypertrophy and fibrosis [ 173 , 174 , 175 , 179 , 180 ].…”

TRAF Molecules in Inflammation and Inflammatory Diseases

“…TRAF6 expression is up-regulated in human atherosclerotic plaques and human hearts with hypertrophic cardiomyopathy, dilated cardiomyopathy, and atrial fibrosis [43,250–252]. Using LDLR −/− mice reconstituted with TRAF6 −/− fetal liver cells and on a high cholesterol diet, Stachon et al reported that TRAF6 is not required for atherogenesis.…”