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) on the myocardium in different heart chambers, comparing the effects of Pb to those of its soluble form. Male rats received intraperitoneal injections of PbO nanoparticle suspension (2.5 mg/kg b.w.) or Pb(CHCOO)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 and Pb(CHCOO) 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 exposure reduced MLC 2 phosphorylation in ventricles. Despite a 2.4-fold lower lead dosage in the Pb, the magnitude of decline in myosin kinetics and MHC ratio shift was comparable between both exposure forms. Thus, Pb 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 exposure. Understanding the molecular mechanisms of influence of Pb exposure on specific heart chambers is essential for developing strategies for reducing cardiovascular morbidity and mortality.