MYOCARDIAL GENE REPROGRAMMING ASSOCIATED WITH A CARDIAC CROSS-RESISTANT STATE INDUCED BY LPS PRECONDITIONING

Lipopolysaccharide (LPS) preconditioning induces cardiac resistance to subsequent LPS or ischemia. This study tested the hypothesis that res istance to LPS and resistance to ischemia are two manifestations of ca rdiac cross-resistance which may involve reprogramming of cardiac gene expression. Rats were preconditioned with a single dose of LPS (0.5 m g/kg ip). Cardiac resistance to LPS was examined with a subsequent LPS challenge. Cardiac resistance to ischemia was determined by subjectin g hearts to ischemia-reperfusion. Total RNA was extracted from myocard ium for Northern analysis of mRNAs encoding protooncoproteins, antioxi dant enzymes, and contractile protein isoforms. Rats preconditioned wi th LPS 1-7 days earlier acquired cardiac resistance to endotoxemic dep ression. This resistance temporally correlated with resistance to isch emia. Pretreatment with cycloheximide (0.5 mg/kg ip) abolished resista nce to both LPS and ischemia. LPS preconditioning induced the expressi on of c-jun, and c-fos mRNAs. LPS also transiently increased mRNAs enc oding catalase and Mn-containing superoxide dismutase. The expression of both alpha- and beta-myosin heavy chain mRNAs was upregulated, wher eas the expression of cardiac a-actin mRNA was suppressed. We conclude that 1) LPS induces sustained cardiac resistance to both LPS and isch emia, 2) resistance to ischemia and resistance to LPS seem to be two m echanistically indistinct components of cardiac cross-resistance, and 3) the cardiac cross-resistance is associated with reprogramming of my ocardial gene expression.