We examined whether apoptosis occurs in cardiomyocytes by hypoxia in vitro. Neonatal rat cardiomyocytes and nonmyocytes were cultured in 95% N2-5% CO2 atmosphere to produce hypoxic conditions. DNA fragmentation into ultraviolet exposure,2,6 anticancer drugs,8-10 viral infection, 11-3 and hyperthermia,14 in a variety of tissues. Ischemia of the heart, which is usually caused by reduction of coronary flow, induces the death of cardiomyocytes and replacement by fibrosis. Although this cardiomyocyte death is classically believed to be induced via necrosis, which is the mechanism of accidental cell death, its precise mechanism remains unclear. It has been recently reported that ischemia induces apoptotic death in the liver15 and in the brain16 in vivo. Thus, in addition to necrotic death, the mechanism of cardiomyocyte death may be involved in the apoptotic process. © 1994 American Heart Association, Inc.myocytes and nonmyocytes as revealed by Northern blotting and in situ hybridization. In hypoxic conditions, Fas messenger RNA levels in cardiomyocytes were upregulated by twofold over controls, whereas those of nonmyocytes were downregulated. These results indicate that cardiomyocyte death by hypoxia can occur via apoptosis and that Fas antigen may be associated with the mechanism of this apoptotic process. (Circ Res. 1994;75:426-433.)

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SUMMARY: Tenascin-C (TNC), an extracellular matrix glycoprotein, plays important roles in tissue remodeling. TNC is not normally expressed in adults but reappears under pathologic conditions. The present study was designed to clarify the contribution of TNC to ventricular remodeling after myocardial infarction. We examined the expression of TNC after experimental myocardial infarction in the rat by immunohistochemistry and in situ hybridization. Within 24 hours of permanent coronary ligation, interstitial fibroblasts in the border zone started to express TNC mRNA. The expression of TNC was down-regulated on Day 7 and was no longer apparent by Day 14 after infarction. During the healing process, TNC protein and TNC-producing cells were found at the edges of the residual myocardium. Some of the TNC-producing cells were immunoreactive for ␣-smooth muscle actin. In culture, TNC increased the number of cardiomyocytes attached to laminin but inhibited the formation of focal contacts at costameres. The results indicate that during the acute phase after myocardial infarction, interstitial cells in the border zone synthesize TNC, which may loosen the strong adhesion of surviving cardiomyocytes to connective tissue and thereby facilitate tissue reorganization. (Lab Invest 2001, 81:1015-1024.T enascins constitute a family of extracellular matrix glycoproteins (Erickson, 1993). The first member found, tenascin-C (TNC), is highly expressed in embryonic tissue during morphogenesis and sparsely expressed in the adult, but reappears during wound healing, regeneration, or cancer invasion (Chiquet-Ehrismann et al, 1986). TNC is transiently expressed in distinct areas in association with active tissue remodeling. Various in vitro findings have indicated that TNC has multiple functions in the regulation of cell migration, proliferation, and apoptosis (Chung et al, 1996;Jones and Jones, 2000). TNC counterbalances cell adhesion to substrata, correlated with cytokinesis and motility, and prevents cells from adhering too tightly to other extracellular matrix proteins (Chiquet-Ehrismann, 1995;Chiquet-Ehrismann et al, 1988;Chung et al, 1996;Murphy-Ullrich et al, 1991;Prieto et al, 1992).In the heart, TNC appears only at very early stages of embryonic development and may play important roles in the differentiation of cardiomyocytes, structural organization of the myocardium, or development of coronary vessels . TNC is not normally expressed in the adult heart but reappears under various pathologic conditions such as dilated cardiomyopathy, myocarditis, or myocardial infarction (Imanaka-Yoshida et al, 1998, 2000Tamura et al, 1996;Willems et al, 1996).To understand its roles in tissue remodeling in the diseased myocardium, we examined the expression of TNC during tissue repair after experimental myocardial infarction in rats. Sequential changes in the localization of the molecule were analyzed by immunohistochemistry, and TNC-producing cells were identified by in situ hybridization (ISH) combined with immunohistochemistry. Additionally, to ...

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Active remodeling of the coronary artery lesions in Kawasaki disease continues in the form of luxuriant intimal proliferation and neoangiogenesis for several years after the onset of the disease. This process is distinct from adult-onset atherosclerosis.

Tenascin-C (TNC) is an extracellular matrix protein which appears at active sites of tissue remodelling during embryogenesis or cancer invasion. In normal heart, TNC is only present during the early stages of development but reappears in pathological states. This study examined the diagnostic value of TNC for assessing disease activity of myocarditis. Expression of TNC was examined in myosin-induced autoimmune myocarditis mouse models. Sequential changes in amount, localization and the producing cells were analysed by reverse transcriptase-polymerase chain reaction, western blotting, immunohistochemistry and in situ hybridization and compared with the histological picture. The expression of TNC was upregulated at a very early stage of myocarditis. Immunostaining was detectable before cell infiltration and myocytolysis became histologically apparent, remained during the active stage while cell infiltration and necrosis continued, and disappeared in scar tissue with healing. TNC immunostaining was always observed at the periphery of necrotic or degenerating cardiomyocytes in foci of inflammation, the expression level correlating with histological evidence of inflammatory activity. Interstitial fibroblasts were the major source of TNC, expressing the large isoform containing alternative splicing sites. These data demonstrate that TNC is a useful marker for evaluation of disease activity in myocarditis.

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