Nano-assault on the heart: Molecular pathways of lead oxide nanoparticle cardiotoxicity

Lead is closely associated with increased cardiovascular risk. We investigated the molecular mechanisms underlying the impact of lead nanoparticle exposure (Pb_NP) on the myocardium in different heart chambers, comparing the effects of Pb_NP to those of its soluble form. Male rats received intraperitoneal injections of PbO nanoparticle suspension (2.5 mg/kg b.w.) or Pb(CH₃COO)₂ solution (6.01 mg/kg b.w.) thrice a week for six weeks. We analyzed sliding velocity of actin, native, and reconstituted thin filaments over myosin, Hill cooperativity and calcium sensitivity of the "pCa-velocity" relationship, relative force by an in vitro motility assay. We determined the isoform content of myosin heavy (MHC) and light chains (MLC), and MLC 2 phosphorylation by gel electrophoresis. Both Pb_NP and Pb(CH₃COO)₂ exposures decreased atrial, right, and left ventricular myosin kinetics, shifted ventricular MHC ratio toward β-MHC with lower kinetics, and reduced atrial MLC 2 phosphorylation; only Pb_NP exposure reduced MLC 2 phosphorylation in ventricles. Despite a 2.4-fold lower lead dosage in the Pb_NP, the magnitude of decline in myosin kinetics and MHC ratio shift was comparable between both exposure forms. Thus, Pb_NP exposure may appear to be more toxic than its soluble counterpart. While certain mechanisms were common to both forms of exposure - decreased myosin kinetics, reduced atrial MLC 2 phosphorylation, shifts in ventricular MHC isoforms - the reduced ventricular MLC 2 phosphorylation emerged as a specific alteration unique to Pb_NP exposure. Understanding the molecular mechanisms of influence of Pb_NP exposure on specific heart chambers is essential for developing strategies for reducing cardiovascular morbidity and mortality.