Abstract 1140: Chronic HIF1a Upregulation Exacerbates Ischemic Cardiomyopathy
Background: Advanced coronary artery disease is characterized by recurrent episodes of myocardial ischemia, and increased levels of hypoxia-inducible factor (HIF) 1a have been documented in the hearts. Although HIF plays essential adaptive roles in the response to ischemia, HIF is also involved in maladaptive responses that contribute to the pathophysiology of some diseases. We hypothesized that chronic HIF1a upregulation may actually exacerbate the development of cardiomyopathy.
Methods: Chronic HIF 1a upregulation in heart was achieved by intramyocardial(IM) injection of adenovirus(Ad) expressing HIF-VP16 to neonatal mice. Ad dsRed was used as control. mRNA levels of atrial natiuretic factor (ANF), BCL2/Ad E1B interacting protein 1 NIP3 (Bnip3) and glucose transporter-1 (Glut-1) were assessed by realtime RT-PCR.
Results: We confirmed that foreign gene expression in hearts can last 4 months post injection. At the dosage of 109 vp/pup, all Ad dsRed-injected pups survived well into adulthood. By contrast, all Ad HIF-injected pups died in 5 days. The dosage of 108 vp/pup was used afterwards. 28.6% Ad HIF-injected pups died in 3 days. Surviving pups were growth-retarded. Body weights (BW) of Ad dsRed- and Ad HIF-injected pups were 1.7±0.1 vs 1.4±0.0g at day 3 (P=0.07), and 7.3±0.2 vs 5.1±0.6g at day 10 (P=0.04). Heart weight/BW ratio was higher in Ad HIF-injected pups at day 10 (5.4±0.2 vs 6.3±0.1 P=0.01). Lipids deposition in Ad HIF-injected heart were shown by Oil Red O staining, suggesting that chronic HIF 1a upregulation lead to lipotoxicity in cardiomyocyte. mRNA levels of ANF, Bnip3 and Glut-1 in Ad HIF-injected hearts were 3.3±0.9, 6.1±0.5, 3.0±1.2 fold higher than those in Ad dsRed-injected hearts (all P<0.05). To test if Ad HIF uptake by liver contributed to growth retardation, growth rate was compared between Ad HIF intrahepatic (IH) injection and IM. BWs of IM pups were lower than IH pups (7.6±1.3 vs 9.6±0.9g at day 15, P=0.02).
Conclusion: These data provide evidence that chronic HIF upregulation, which is found in the hearts of patients with ischemic cardiomyopathy, can exacerbate myocardial dysfunction and lead to lipid accumulation. The findings suggest another important pathway in the pathogenesis of ischemic cardiomyopathy and heart failure.