In rat cardiac myocytes, TNFR2 signaling exerted a protective role against TNFalpha-induced ROS production and cell death, acting as a critical limiting factor on predominant TNFR1 responses.
Does TNFalpha signaling through TNFR1 and TNFR2 alter ROS production, calcium transients, and cell survival in rat cardiac myocytes?
The study demonstrates that TNFR2 signaling plays a protective role in cardiac myocytes, counteracting the detrimental effects of TNFR1, and suggests NAC as a tool to selectively neutralize TNFR1 effects.
Tumor necrosis factor alpha (TNFalpha) plays a major role in chronic heart failure, signaling through two different receptor subtypes, TNFR1 and TNFR2. Our aim was to further delineate the functional role and signaling pathways related to TNFR1 and TNFR2 in cardiac myocytes. In cardiac myocytes isolated from control rats, TNFalpha induced ROS production, exerted a dual positive and negative action on Ca(2+) transient and cell fractional shortening, and altered cell survival. Neutralizing anti-TNFR2 antibodies exacerbated TNFalpha responses on ROS production and cell death, arguing for a major protective role of the TNFR2 pathway. Treatment with either neutralizing anti-TNFR1 antibodies or the glutathione precursor, N-acetylcysteine (NAC), favored the emergence of TNFR2 signaling that mediated a positive effect of TNFalpha on Ca(2+) transient and cell fractional shortening. The positive effect of TNFalpha relied on TNFR2-dependent activation of the cPLA(2) activity, independently of serine 505 phosphorylation of the enzyme. Together with cPLA(2) redistribution and AA release, TNFalpha induced a time-dependent phosphorylation of ERK, MSK1, PKCzeta, CaMKII, and phospholamban on the threonine 17 residue. Taken together, our results characterized a TNFR2-dependent signaling and illustrated the close interplay between TNFR1 and TNFR2 pathways in cardiac myocytes. Although apparently predominant, TNFR1-dependent responses were under the yoke of TNFR2, acting as a critical limiting factor. In vivo NAC treatment proved to be a unique tool to selectively neutralize TNFR1-mediated effects of TNFalpha while releasing TNFR2 pathways.
Defer et al. (Thu,) conducted a other in Heart failure (cellular mechanisms). TNFalpha, anti-TNFR1/TNFR2 antibodies, N-acetylcysteine (NAC) vs. Control was evaluated on ROS production, [Ca(2+)] transient, cell fractional shortening, and cell survival. In rat cardiac myocytes, TNFR2 signaling exerted a protective role against TNFalpha-induced ROS production and cell death, acting as a critical limiting factor on predominant TNFR1 responses.