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A great number of studies indicate that cardiac fibroblasts are essential for maintaining the structure and function of heart. Hypoxia-inducible factor-1 alpha (HIF-1α) is a central transcriptional regulator of hypoxic response. The present study examined whether over-expression of HIF-1α could prevent hypoxia-induced injury in neonatal rat cardiac fibroblasts and, if so, its possible molecular targets.Western blotting was used to detect protein level. MTT, electron microscopy, TUNEL staining and confocal microscopy were used to identify cell viability, cell apoptosis and intracellular calcium ([Ca2+]i) in cardiac fibroblasts, respectively.When cardiac fibroblasts were exposed to hypoxia, HIF-1α protein in nuclei was transiently accumulated at 1 h, and then gradually degraded within 24 h of hypoxia exposure. Over-expression of HIF-1α enhanced nucleus expression of HIF-1α in cardiac fibroblasts, and significantly abolished the decrease of cell viability and cell apoptosis caused by 24-h hypoxia. Accordingly, hypoxia-induced Bax up-regulation, Bcl-2 down-regulation, caspase-3 activation and overload of [Ca2+]i in cardiac fibroblasts were reversed by HIF-1α over-expression, but were promoted by 30 μmol/l SC205346, a specific HIF-1α blocker.Our results indicate that HIF-1α may act as a protective factor in the apoptotic process of cardiac fibroblasts and represent a potential therapeutic target for heart remodeling after hypoxia injury.