Molecular Biology of the Coronary Vascular and Myocardial Responses to Ischemia

Abstract

To understand the complex mechanism(s) involved in molecular responses to ischemia, we developed two experimental models in pigs. In a "stunning" model of repetitive ischemia and reperfusion, we studied the mRNA expression of immediate early genes like c-fos, c-myc and heat shock protein-70 (HSP-70). Myocardial stunning was achieved by two cycles of 10-min left anterior descending coronary artery (LAD) occlusion and 30 min reperfusion. We observed several-fold enhanced expression of c-fos and HSP-70 mRNA in the stunned myocardium as compared with the control, whereas c-myc mRNA levels remained almost unchanged. In the second model, we examined the expression of the peptide mitogens heparin-binding growth factor 1 (HBGF-1) and transforming growth factor beta 1 (TGF-beta 1) after a chronic coronary artery occlusion leading to myocardial collateralization. Progredient stenosis of the circumflex coronary artery was induced by implanting a hygroscopic ameroid constrictor ring around it and occlusion was verified by in vivo angiography. Using polymerase chain reaction (PCR) and Northern hybridization techniques, we observed significantly enhanced expression of HBGF-1 and TGF-beta 1 in collateralized myocardium as compared with normal. In situ techniques revealed the localization of HBGF-1 transcripts in the blood vessel wall, and TGF-beta 1 in cardiac myocytes and Purkinje cells. Our results clearly indicate that myocardial stunning stimulates the expression of transcription factors which might be involved in regulation of certain growth factors like HBGF-1 and TGF-beta 1 which may play a significant role in the development of a collateral circulation.