Therapies aimed at enhancing cardiomyocyte survival following myocardial injury are urgently required. As GHRP6 [GH (growth hormone)-releasing peptide 6] has been shown to stimulate GH secretion and has beneficial cardiovascular effects, the aim of the present study was to determine whether GHRP6 administration reduces myocardial infarct size following acute coronary occlusion in vivo. Female Cuban Creole pigs were anaesthetized, monitored and instrumented to ensure a complete sudden left circumflex artery occlusion for 1 h, followed by a 72 h reperfusion/survival period. Animals were screened clinically before surgery and assigned randomly to receive either GHRP6 (400 microg/kg of body weight) or normal saline. Hearts were processed, and the area at risk and the infarct size were determined. CK-MB (creatine kinase MB) and CRP (C-reactive protein) levels and pathological Q-wave-affected leads were analysed and compared. Evaluation of the myocardial effect of GHRP6 also included quantitative histopathology, local IGF-I (insulin-growth factor-I) expression and oxidative stress markers. GHRP6 treatment did not have any influence on mortality during surgery associated with rhythm and conductance disturbances during ischaemia. Infarct mass and thickness were reduced by 78% and 50% respectively, by GHRP6 compared with saline (P<0.01). More than 50% of the GHRP6-treated pigs did not exhibit pathogological Q waves in any of the ECG leads. Quantitative histopathology and CK-MB and CRP serum levels confirmed the reduction in GHRP6-mediated necrosis (all P<0.05). Levels of oxidative stress markers suggested that GHRP6 prevented myocardial injury via a decrease in reactive oxygen species and by the preservation of antioxidant defence systems (all P<0.05). Myocardial IGF-I transcription was not amplified by GHRP6 treatment compared with the increase induced by the ischaemic episode in relation to expression in intact hearts (P<0.01). In conclusion, GHRP6 exhibits antioxidant effects which may partially contribute to reduce myocardial ischaemic damage.
A gene encoding a multiepitope polypeptide (MEP) has been synthesized. It contains the information for (1) an 11-amino acid (aa) epitope from the C1 region of gp120 of HIV-1 and (2) 3 epitopes of 15 amino acids each, from the central part of the V3 loop of isolates MN, SC, and WMJII. These four segments are linked by the short spacer peptide AGGGA. This gene was cloned in a plasmid vector and expressed in Escherichia coli as a fusion product with a 62-aa fragment of human IL-2. The recombinant protein TAB1 was purified by washed pellet procedures and reversed-phase HPLC. TAB1 was recognized in ELISAs by 25 of 27 sera from seropositive individuals. Mice were immunized and several hybridomas were obtained. Two of them secrete monoclonal antibodies that react with synthetic peptides from isolates MN, WMJI, WMJIII, and SC with an affinity constant in the range of 10(8) M-1. They also recognized peptides from isolates SF2 and WMJII, but at much lower affinity. The results obtained from peptide ELISAs indicate that the putative epitope recognized by these MAbs lies within the sequence IHIGPGRAFYT. Classic neutralization assays demonstrated that MAb 2C4 neutralizes 50% of the MN isolate at 0.6 micrograms/ml but fails to neutralize IIIB and SF2 strains. The presence of antibodies directed against every one of the component peptides in the sera of rabbits immunized with TAB1 was also documented.
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