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

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.