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Monophosphoryl lipid A induces pharmacologic ‘preconditioning’ in rabbit hearts without concomitant expression of 70-kDa heat shock protein

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Abstract

The purpose of this study was to evaluate the protective effect of a new endotoxin analogue, monophosphoryl lipid A (MLA) in a rabbit model of myocardial ischemia/reperfusion and to show if this protection was mediated via synthesis of 70 kDa heat shock protein (HSP 70). Three groups of New Zealand White rabbits underwent 30 min coronary occlusion, followed by 4 hours reperfusion. First group of rabbits (n = 6) were treated with 0.35 ml vehicle (40 % propylene glycol, 10% ethanol in water). The second and third group of rabbits (n = 6–8) were treated with MLA (35 μg/kg, i.v.) 12 and 24 hours prior to ischemia and reperfusion. MLA treatment either 12 or 24 h prior to ischemia/reperfusion demonstrated significantly reduced infarct size (12.5 ± 1.7 and 14.7 ± 2.1 % for 12 and 24 h) when compared with vehicle control (40.4 ± 8.6%, mean ± S.E.M, p < 0.05). No significant differences in the infarct size was observed between the 12 and 24 h MLA treated groups. The area at risk was not significantly different between the three groups. Baseline values of heart rate, systolic and diastolic blood pressure were not significantly different between the control and MLA treated groups. However, the systolic as well as diastolic blood pressure during reperfusion were significantly lower in rabbits treated with MLA. Western blot analysis of the protein extracts of the hearts (n = 2/group) demonstrated no increase in the expression of the inducible form of HSP 70 following treatment with MLA. We conclude that MLA has significant anti-infarct effect in rabbit which is not mediated by the cardioprotective protein HSP 70. The anti-infarct effect of this drug is superior to the reported protective effects of delayed ischemic or heat stress preconditioning. We hypothesize that the pharmacologic preconditioning afforded by MLA is accomplished via a unique pathway that bypasses the usual intracellular signaling pathways which lead to the myocardial protection with the expression of heat shock proteins.

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Authors and Affiliations

  1. Division of Cardiology, Medical College of Virginia, Virginia Commonwealth University, 23298, Richmond, VA, USA

    Mohammed M. Maaieh, Joshua B. Shipley, Mark Doloresco, Nelson L. Bernardo, Yong-Zhen Qian & Rakesh C. Kukreja (Eric Lipman Associate Professor of Medicine)

  2. Department of Anesthesiology, Kanagawa Dental College, 238, Kanagawa, Japan

    Kazu-ichi Yoshida

  3. RIBI ImmunoChem Research Inc., 59840, Hamilton, MT, USA

    Gary T. Elliott

Authors
  1. Kazu-ichi Yoshida
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  2. Mohammed M. Maaieh
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  3. Joshua B. Shipley
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  4. Mark Doloresco
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  5. Nelson L. Bernardo
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  6. Yong-Zhen Qian
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  7. Gary T. Elliott
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  8. Rakesh C. Kukreja
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Additional information

A preliminary form of this paper was presented at the XV World Congress of the International Society for Heart Research held in Prague, Czech Republic [17]. This work was supported in part by grants HL 46763 and 51045 from National Institutes of Health and a grant from RIBI ImmunoChem Research, Hamilton, Montana. JBS was supported from a training grant HL 07537 from National Institutes of Health.

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Yoshida, Ki., Maaieh, M.M., Shipley, J.B. et al. Monophosphoryl lipid A induces pharmacologic ‘preconditioning’ in rabbit hearts without concomitant expression of 70-kDa heat shock protein. Mol Cell Biochem 156, 1–8 (1996). https://doi.org/10.1007/BF00239312

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  • DOI: https://doi.org/10.1007/BF00239312

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