Adrenergic induction of bimodal myocardial protection: signal transduction and cardiac gene reprogramming

Abstract

This study tested the hypothesis that in vivo norepinephrine (NE) treatment induces bimodal cardiac functional protection against ischemia and examined the roles of α1-adrenoceptors, protein kinase C (PKC), and cardiac gene expression in cardiac protection. Rats were treated with NE (25 μg/kg iv). Cardiac functional resistance to ischemia-reperfusion (25/40 min) injury was examined 30 min and 1, 4, and 24 h after NE treatment with the Langendorff technique, and effects of α1-adrenoceptor antagonism and PKC inhibition on the protection were determined. Northern analysis was performed to examine cardiac expression of mRNAs encoding α-actin and myosin heavy chain (MHC) isoforms. Immunofluorescent staining was performed to localize PKC-βI in the ventricular myocardium. NE treatment improved postischemic functional recovery at 30 min, 4 h, and 24 h but not at 1 h. Pretreatment with prazosin or chelerythrine abolished both the early adaptive response at 30 min and the delayed adaptive response at 24 h. NE treatment induced intranuclear translocation of PKC-βI in cardiac myocytes at 10 min and increased skeletal α-actin and β-MHC mRNAs in the myocardium at 4–24 h. These results demonstrate that in vivo NE treatment induces bimodal myocardial functional adaptation to ischemia in a rat model. α1-Adrenoceptors and PKC appear to be involved in signal transduction for inducing both the early and delayed adaptive responses. The delayed adaptive response is associated with the expression of cardiac genes encoding fetal contractile proteins, and PKC-βI may transduce the signal for reprogramming of cardiac gene expression.

Inhibition of Endogenous Hedgehog Signaling Protects Against Acute Liver Injury After Ischemia Reperfusion

“…However, strong upregulation of Shh, Ptch-1 and Gli-1 ligands in areas around the portal tracts were seen as early as 1 h after I/R injury. Our findings are in good accordance with the literature describing recruitment and engagement of embryonic signaling pathways following ischemia reperfusion (31).…”

Postnatal Recapitulation of Embryonic Hedgehog Pathway in Response to Skeletal Muscle Ischemia

“…These findings are consistent with previous reports in the literature describing the association of both ischemia and tissue regeneration with the reactivation of genes involved in fetal transcription programs. [33][34][35] After ischemia, Ptc1 expression occurs in interstitial mesenchymal fibroblasts. The ability of fibroblasts to respond to Shh stimulation has already been demonstrated: eg, fibroblasts respond to Shh stimulation in vitro, 21 physiologically express Ptc1 in adult perineural sheaths and dermis, 6,9 and upregulate Ptc1 and VEGF during Shh-induced corneal neo- Immunostaining for Shh and Ptc1 in ischemic regenerating skeletal muscle.…”

Exercise directly enhances myocardial tolerance to ischaemia-reperfusion injury in the rat through a protein kinase C mediated mechanism

“…Reactive oxygen species may activate protein kinase C independently of G proteins and could be generated during moderate exercise. δ-Opioid receptor stimulation with synthetic analogues is known to protect rat myocardium against infarction 24–48 hours later30 and bolus dosing with noradrenaline has been shown to induce delayed cardioprotection in rat heart through an α 1 adrenoreceptor mediated mechanism 31. As release of endogenous opioid peptides, particularly endorphins, is of special interest in relation to exercise, the participation of endorphins could be examined in subsequent studies.…”