Valsartan Reduced Atrial Fibrillation Susceptibility by Inhibiting Atrial Parasympathetic Remodeling through MAPKs/Neurturin Pathway

Abstract

Background/Aims: Angiotensin II receptor blockers (ARBs) have been proved to be effective in preventing atrial structural and electrical remodelinq in atrial fibrillation (AF). Previous studies have shown that parasympathetic remodeling plays an important role in AF. However, the effects of ARBs on atrial parasympathetic remodeling in AF and the underlying mechanisms are still unknown. Methods: Canines were divided into sham-operated, pacing and valsartan + pacing groups. Rats and HL-1 cardiomyocytes were divided into control, angiotensin II (Ang II) and Ang II + valsartan groups, respectively. Atrial parasympathetic remodeling was quantified by immunocytochemical staining with anti-choline acetyltransferase (ChAT) antibody. Western blot was used to analysis the protein expression of neurturin. Results: Both inducibility and duration were increased in chronic atrial rapid-pacing canine model, which was significantly inhibited by the treatment with valsartan. The density of ChAT-positive nerves and the protein level of neurturin in the atria of pacing canines were both increased than those in sham-operated canines. Ang II treatment not only induced atrial parasympathetic remodeling in rats, but also up-regulated the protein expression of neurturin. Valsartan significantly prevented atrial parasympathetic remodeling, and suppressed the protein expression of neurturin. Meanwhile, valsartan inhibited Ang II -induced up-regulation of neurturin and MAPKs in cultured cardiac myocytes. Inhibition of MAPKs dramatically attenuated neurturin up-regulation induced by Ang II. Conclusion: Parasympathetic remodeling was present in animals subjected to rapid pacing or Ang II infusion, which was mediated by MAPKs/neurturin pathway. Valsartan is able to prevent atrial parasympathetic remodeling and the occurrence of AF via inhibiting MAPKs/neurturin pathway.

Atrial fibrosis underlying atrial fibrillation (Review)

“…DAG activates protein kinase C, which in turn activates extracellular-signal-regulated kinases (ERKs). In addition, acting as a potent NADPH oxidase activator, Ang II induces ROS overproduction, which, in-turn, activates multiple downstream second messengers, including MAPK, nuclear factor-κB and cytokines (52,53). Through the activation of the MAPK signalling pathway, Ang II promotes the secretion of TGF-β 1 .…”

Angiotensin II affects inflammation mechanisms via AMPK-related signalling pathways in HL-1 atrial myocytes

“…Ang II induces reactive oxygen species (ROS) generation, which activates multiple intracellular second messenger molecules such as mitogen-activated protein kinases (MAPK), transforming growth factor-β1 (TGF-β1), nuclear factor-κB (NF-κB), and cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor α (TNFα) 11 , 12 . The MAPK pathway, including c-Jun N-terminal kinase (JNK) activation, is associated with various pathological conditions such as cancer, stroke, inflammatory disease, and heart failure 13 , 14 .…”

Transcriptome analysis reveals key pathways that vary in patients with paroxysmal and persistent atrial fibrillation

“…Zhang et al (43) revealed that the MAPKs/TGF-β1/TRAF6 signaling pathways participate in atrial fibrosis in patients with rheumatic heart disease, causing the occurrence of AF following cardiac surgery. Inhibiting the MAPK pathways can prevent atrial parasympathetic remodeling and the occurrence of AF (44). The induction of AF and structural remodeling was associated with MAPK expression and the decrease in collagenase activity (15).…”