Molecular Mechanisms of Effects of Lead and Cadmium Co-exposure on Atrial and Ventricular Myocardium: Soluble Salts Versus Nanoparticles.

Abstract

Lead (Pb) and cadmium (Cd) are ubiquitous xenobiotics associated with cardiovascular diseases. While Pb and Cd cardiotoxicity is well studied, the molecular mechanisms of their co-exposure are poorly understood. We aimed to investigate the cardiotoxic effects of subchronic co-exposure to soluble versus nanoparticle forms of Pb and Cd on the atrial and ventricular myocardium. Rats received 18 intraperitoneal injections of combined Pb(C₂H₃O₂)₂ (6.01 mg/kg b.w.) and CdCl₂ (0.377 mg/kg b.w.) solution over 6 weeks (Pb+Cd group). Another group received 18 injections of combined PbO (2.32 mg/kg b.w.) and CdO (0.22 mg/kg b.w.) nanoparticle (NP) suspension (Pb_NP+Cd_NP group) over 6 weeks. We examined the relative force, sliding velocity of actin and regulated thin filaments over myosin, the fraction of motile filaments, and the characteristics of the "pCa-velocity" and "pCa-fraction of motile filaments" relationships using an in vitro motility assay. We analyzed myosin heavy (MHC) and light (MLC) chains' isoform composition and regulatory light chain (MLC2) phosphorylation by SDS-PAGE. In the Pb+Cd group, atrial and left-ventricular (LV) myosin kinetics was reduced but right-ventricular (RV) myosin kinetics was increased. The MHC ratio shifted toward α-MHC in the RV and toward β-MHC in the LV, and MLC2 phosphorylation in the atria was increased. In the Pb_NP+Cd_NP group, myosin kinetics was reduced in all heart chambers, and the MHC ratio shifted toward the β-isoform in the ventricles. The effects of co-exposure to Pb and Cd differ from those of isolated exposures and depend on the chemical forms of the toxicants and the specific heart chamber.