This study found that (1) MPO might provoke vascular endothelial dysfunction in hypercholesterolemic rats by reducing NO biological activity and impairing the NO/cGMP/cGK signaling pathway and (2) the PPARγ agonist PIO might inhibit vascular MPO activity and increase NO bioavailability with the net result of reversing endothelial dysfunction in hypercholesterolemic rats. This evidence concerns the gene PRKG1 and endothelial dysfunction.