Abstract
Brief ischemic periods lead to myocardial dysfunction without myocardial infarction. It has been shown that expression of inducible HSP70 in hearts of transgenic mice leads to decreased infarct size, but it remains unclear if HSP70 can also protect against myocardial dysfunction after brief ischemia. To investigate this question, we developed a mouse model in which regional myocardial function can be measured before and after a temporary ischemic event in vivo. In addition, myocardial function was determined after brief episodes of global ischemia in an isolated Langendorff heart. HSP70-positive mice and transgene negative littermates underwent 8 min of regional myocardial ischemia created by occlusion of the left descending coronary artery, followed by 60 min of reperfusion. This procedure did not result in a myocardial infarction. Regional epicardial strain was used as a sensitive indicator for changes in myocardial function after cardiac ischemia. Maximum principal strain was significantly greater in HSP70-positive mice with 88+/-6% of preischemic values vs. 58+/-6% in transgene-negative mice (P < 0.05). Similarly, in isolated Langendorff perfused hearts of HSP70-positive and transgene-negative littermates exposed to 10 min of global ischemia and 90 min of reperfusion, HSP70 transgenic hearts showed a better-preserved ventricular peak systolic pressure. Thus, we conclude that expression of HSP70 protects against postischemic myocardial dysfunction as shown by better preserved myocardial function.
Full Text
The Full Text of this article is available as a PDF (253.2 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Bolli R. Mechanism of myocardial "stunning". Circulation. 1990 Sep;82(3):723–738. doi: 10.1161/01.cir.82.3.723. [DOI] [PubMed] [Google Scholar]
- Braunwald E., Kloner R. A. The stunned myocardium: prolonged, postischemic ventricular dysfunction. Circulation. 1982 Dec;66(6):1146–1149. doi: 10.1161/01.cir.66.6.1146. [DOI] [PubMed] [Google Scholar]
- Currie R. W. Effects of ischemia and perfusion temperature on the synthesis of stress-induced (heat shock) proteins in isolated and perfused rat hearts. J Mol Cell Cardiol. 1987 Aug;19(8):795–808. doi: 10.1016/s0022-2828(87)80390-5. [DOI] [PubMed] [Google Scholar]
- Currie R. W., Karmazyn M., Kloc M., Mailer K. Heat-shock response is associated with enhanced postischemic ventricular recovery. Circ Res. 1988 Sep;63(3):543–549. doi: 10.1161/01.res.63.3.543. [DOI] [PubMed] [Google Scholar]
- Dillmann W. H., Mehta H. B., Barrieux A., Guth B. D., Neeley W. E., Ross J., Jr Ischemia of the dog heart induces the appearance of a cardiac mRNA coding for a protein with migration characteristics similar to heat-shock/stress protein 71. Circ Res. 1986 Jul;59(1):110–114. doi: 10.1161/01.res.59.1.110. [DOI] [PubMed] [Google Scholar]
- Donnelly T. J., Sievers R. E., Vissern F. L., Welch W. J., Wolfe C. L. Heat shock protein induction in rat hearts. A role for improved myocardial salvage after ischemia and reperfusion? Circulation. 1992 Feb;85(2):769–778. doi: 10.1161/01.cir.85.2.769. [DOI] [PubMed] [Google Scholar]
- Ellis J. Proteins as molecular chaperones. 1987 Jul 30-Aug 5Nature. 328(6129):378–379. doi: 10.1038/328378a0. [DOI] [PubMed] [Google Scholar]
- Ferguson J. J. American College of Cardiology 45th Annual Scientific Session, Orlando, Florida, March 24 to 27, 1996. Circulation. 1996 Jul 1;94(1):1–5. doi: 10.1161/01.cir.94.1.1. [DOI] [PubMed] [Google Scholar]
- Ganz W., Watanabe I., Kanamasa K., Yano J., Han D. S., Fishbein M. C. Does reperfusion extend necrosis? A study in a single territory of myocardial ischemia--half reperfused and half not reperfused. Circulation. 1990 Sep;82(3):1020–1033. doi: 10.1161/01.cir.82.3.1020. [DOI] [PubMed] [Google Scholar]
- Gao W. D., Atar D., Backx P. H., Marban E. Relationship between intracellular calcium and contractile force in stunned myocardium. Direct evidence for decreased myofilament Ca2+ responsiveness and altered diastolic function in intact ventricular muscle. Circ Res. 1995 Jun;76(6):1036–1048. doi: 10.1161/01.res.76.6.1036. [DOI] [PubMed] [Google Scholar]
- Hess M. L., Kukreja R. C. Free radicals, calcium homeostasis, heat shock proteins, and myocardial stunning. Ann Thorac Surg. 1995 Sep;60(3):760–766. doi: 10.1016/0003-4975(95)00574-5. [DOI] [PubMed] [Google Scholar]
- Heyndrickx G. R., Millard R. W., McRitchie R. J., Maroko P. R., Vatner S. F. Regional myocardial functional and electrophysiological alterations after brief coronary artery occlusion in conscious dogs. J Clin Invest. 1975 Oct;56(4):978–985. doi: 10.1172/JCI108178. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hoshida S., Kuzuya T., Fuji H., Yamashita N., Oe H., Hori M., Suzuki K., Taniguchi N., Tada M. Sublethal ischemia alters myocardial antioxidant activity in canine heart. Am J Physiol. 1993 Jan;264(1 Pt 2):H33–H39. doi: 10.1152/ajpheart.1993.264.1.H33. [DOI] [PubMed] [Google Scholar]
- Hutter J. J., Mestril R., Tam E. K., Sievers R. E., Dillmann W. H., Wolfe C. L. Overexpression of heat shock protein 72 in transgenic mice decreases infarct size in vivo. Circulation. 1996 Sep 15;94(6):1408–1411. doi: 10.1161/01.cir.94.6.1408. [DOI] [PubMed] [Google Scholar]
- Ji L. L., Fu R. G., Waldrop T. G., Liu K. J., Swartz H. M. Myocardial response to regional ischemia and reperfusion in vivo in rat heart. Can J Physiol Pharmacol. 1993 Oct-Nov;71(10-11):811–817. doi: 10.1139/y93-121. [DOI] [PubMed] [Google Scholar]
- Knowlton A. A., Brecher P., Apstein C. S. Rapid expression of heat shock protein in the rabbit after brief cardiac ischemia. J Clin Invest. 1991 Jan;87(1):139–147. doi: 10.1172/JCI114963. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lew W. Y., Nishikawa Y., Su H. Cardiac myocyte function and left ventricular strains after brief ischemia and reperfusion in rabbits. Circulation. 1994 Oct;90(4):1942–1950. doi: 10.1161/01.cir.90.4.1942. [DOI] [PubMed] [Google Scholar]
- Li X. Y., McCay P. B., Zughaib M., Jeroudi M. O., Triana J. F., Bolli R. Demonstration of free radical generation in the "stunned" myocardium in the conscious dog and identification of major differences between conscious and open-chest dogs. J Clin Invest. 1993 Aug;92(2):1025–1041. doi: 10.1172/JCI116608. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Locke M., Tanguay R. M., Klabunde R. E., Ianuzzo C. D. Enhanced postischemic myocardial recovery following exercise induction of HSP 72. Am J Physiol. 1995 Jul;269(1 Pt 2):H320–H325. doi: 10.1152/ajpheart.1995.269.1.H320. [DOI] [PubMed] [Google Scholar]
- Manché A., Edmondson S. J., Hearse D. J. Dynamics of early postischemic myocardial functional recovery. Evidence of reperfusion-induced injury? Circulation. 1995 Aug 1;92(3):526–534. doi: 10.1161/01.cir.92.3.526. [DOI] [PubMed] [Google Scholar]
- Marber M. S., Mestril R., Chi S. H., Sayen M. R., Yellon D. M., Dillmann W. H. Overexpression of the rat inducible 70-kD heat stress protein in a transgenic mouse increases the resistance of the heart to ischemic injury. J Clin Invest. 1995 Apr;95(4):1446–1456. doi: 10.1172/JCI117815. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mehta H. B., Popovich B. K., Dillmann W. H. Ischemia induces changes in the level of mRNAs coding for stress protein 71 and creatine kinase M. Circ Res. 1988 Sep;63(3):512–517. doi: 10.1161/01.res.63.3.512. [DOI] [PubMed] [Google Scholar]
- Mestril R., Chi S. H., Sayen M. R., Dillmann W. H. Isolation of a novel inducible rat heat-shock protein (HSP70) gene and its expression during ischaemia/hypoxia and heat shock. Biochem J. 1994 Mar 15;298(Pt 3):561–569. doi: 10.1042/bj2980561. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Michael L. H., Entman M. L., Hartley C. J., Youker K. A., Zhu J., Hall S. R., Hawkins H. K., Berens K., Ballantyne C. M. Myocardial ischemia and reperfusion: a murine model. Am J Physiol. 1995 Dec;269(6 Pt 2):H2147–H2154. doi: 10.1152/ajpheart.1995.269.6.H2147. [DOI] [PubMed] [Google Scholar]
- Milano C. A., Allen L. F., Rockman H. A., Dolber P. C., McMinn T. R., Chien K. R., Johnson T. D., Bond R. A., Lefkowitz R. J. Enhanced myocardial function in transgenic mice overexpressing the beta 2-adrenergic receptor. Science. 1994 Apr 22;264(5158):582–586. doi: 10.1126/science.8160017. [DOI] [PubMed] [Google Scholar]
- Neely J. R., Liebermeister H., Battersby E. J., Morgan H. E. Effect of pressure development on oxygen consumption by isolated rat heart. Am J Physiol. 1967 Apr;212(4):804–814. doi: 10.1152/ajplegacy.1967.212.4.804. [DOI] [PubMed] [Google Scholar]
- Nguyen V. T., Morange M., Bensaude O. Protein denaturation during heat shock and related stress. Escherichia coli beta-galactosidase and Photinus pyralis luciferase inactivation in mouse cells. J Biol Chem. 1989 Jun 25;264(18):10487–10492. [PubMed] [Google Scholar]
- Omens J. H., Farr D. D., McCulloch A. D., Waldman L. K. Comparison of two techniques for measuring two-dimensional strain in rat left ventricles. Am J Physiol. 1996 Sep;271(3 Pt 2):H1256–H1261. doi: 10.1152/ajpheart.1996.271.3.H1256. [DOI] [PubMed] [Google Scholar]
- Opie L. H. Reperfusion injury and its pharmacologic modification. Circulation. 1989 Oct;80(4):1049–1062. doi: 10.1161/01.cir.80.4.1049. [DOI] [PubMed] [Google Scholar]
- Patel B., Kloner R. A., Przyklenk K., Braunwald E. Postischemic myocardial "stunning": a clinically relevant phenomenon. Ann Intern Med. 1988 Apr;108(4):626–628. doi: 10.7326/0003-4819-108-4-626. [DOI] [PubMed] [Google Scholar]
- Sun J. Z., Tang X. L., Knowlton A. A., Park S. W., Qiu Y., Bolli R. Late preconditioning against myocardial stunning. An endogenous protective mechanism that confers resistance to postischemic dysfunction 24 h after brief ischemia in conscious pigs. J Clin Invest. 1995 Jan;95(1):388–403. doi: 10.1172/JCI117667. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Villarreal F. J., Lew W. Y., Waldman L. K., Covell J. W. Transmural myocardial deformation in the ischemic canine left ventricle. Circ Res. 1991 Feb;68(2):368–381. doi: 10.1161/01.res.68.2.368. [DOI] [PubMed] [Google Scholar]
- Villarreal F. J., Waldman L. K., Lew W. Y. Technique for measuring regional two-dimensional finite strains in canine left ventricle. Circ Res. 1988 Apr;62(4):711–721. doi: 10.1161/01.res.62.4.711. [DOI] [PubMed] [Google Scholar]