Myofibroblasts in reperfused myocardial infarcts express the embryonic form of smooth muscle myosin heavy chain (SMemb).
OBJECTIVE
The purpose of this study is to examine the cellular content of healing myocardial infarcts and study the phenotypic characteristics of fibroblasts during scar formation utilizing a canine model of coronary occlusion and reperfusion.


METHODS
Ischemia/Reperfusion experiments were performed in dogs undergoing 1 h of coronary occlusion followed by reperfusion intervals ranging from 5 h to 28 days. Fibrotic and control areas were studied using immunohistochemistry.


RESULTS
The healing ischemic and reperfused myocardium demonstrated significant proliferative activity peaking after 3 to 7 days of reperfusion, predominantly in myofibroblasts. The numbers of proliferating cells decreased during the maturation phase of the scar (PCNA index: 13.7+/-2.25% at 5 days vs. 4.8+/-1.1% at 28 days; P<0.05, n=5). During the proliferative phase of healing (3-7 days) alpha-smooth muscle actin (alpha-SMAc) expression was markedly increased in the fibrotic areas. alpha-SMAc predominantly localized in myofibroblasts which were vimentin positive, smooth muscle myosin, calponin and desmin negative. We examined expression of smooth muscle myosin heavy chain isoforms in myofibroblasts infiltrating the healing areas and found a marked induction of the embryonal isoform of myosin heavy chain (SMemb) in alpha-SMAc positive spindle shaped cells in the border of the scar. Myofibroblasts did not express SM2, a marker for mature smooth muscle cells. In contrast myocardial arterioles were positive for SM2, but did not express SMemb.


CONCLUSIONS
Healing myocardial infarcts undergo rapid changes in their content of myofibroblasts. During the proliferative phase fibroblasts undergo phenotypic changes leading to expression of contractile proteins such as alpha-SMAc, and production of SMemb, a marker for dedifferentiated smooth muscle cells. Expression of embryonic isoforms indicates dedifferentiation and allows the myofibroblast pool to serve as a versatile cell population, assuming different phenotypes depending on the physiological needs.
Frangogiannis
N G
NG
Section of Cardiovascular Sciences, Baylor College of Medicine and the De Bakey Heart Center, The Methodist Hospital, Houston TX, USA. ngf@bcm.tmc.edu
Michael
L H
LH
Entman
M L
ML
D000818:Animals; D004285:Dogs; D005260:Female; D005355:Fibrosis; D007150:Immunohistochemistry; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000737:chemistry* / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D013997:Time Factors
D018809:Proliferating Cell Nuclear Antigen