Abstract 15165: Sterol Regulatory Element-Binding Protein-1 Participates in the Development of Cardiac Injury Partly via Chronic Inflammation
Background: Sterol regulatory element-binding protein (SREBP)-1, which is a transcription factor positively regulating triglyceride synthesis, contributes to organ damages in the liver and kidney; one of phenotypes is represented by fibrotic infiltration. However, it is unclear whether SREBP-1 contributes to the cardiac pathogenesis.
Purpose: To elucidate whether SREBP-1 contributes to the development of cardiac injury.
Methods and Results: We made hypertension and cardiac hypertrophy model by 2-week infusion of angiotensin II (A-II) (1.44 mg/kg body weight/day). Mice were divided into followings (n=5∼6 in each group): wild with vehicle (WC), wild with A-II (WA), SREBP-1 knockout mice (SREBP-KO) with vehicle (SC), and SREBP-KO with A-II (SA). WA and SA showed significant elevation in blood pressure and cardiac hypertrophy compared to WC and SC, respectively. Ejection fraction (EF) was significantly lower in WA than in WC (71±2 % vs 80±2 %, P<0.05); however, EF was preserved in SA compared to SC (76±2% vs 78±3 %, P=NS). Mature form of SREBP-1 protein in hearts is significantly increased in WA compared with WC, suggesting that SREBP-1 pathway is activated by A-II. Severe perivascular fibrosis was observed in WA; however, there was no difference between in SA and SC. We analyzed gene expression by DNA microarray using the software GenMAPP and MAPPFinder to find gene clusters and pathways mostly illustrative for these phenotypes. Gene expression of collagens (Col1a, 3a) and extracellular matrix (fibromodulin, periostin) was increased in WA as we assumed. Highly scored annotations were clusters of chemokine receptors (CCRs 2, 3, 5), interleukin responses (IL-1b, IL-13, IL-16), and growth factors (TGFb2, VEGF), suggesting that inflammatory and repairing responses occurred in WA. These expression patterns were normalized in SA compared with SC. Furthermore, expression of antioxidant gene, Nrf2, HO-1, and NQO1, was decreased in WA compared to WC; meanwhile, there is no difference between in SA and SC.
Conclusion: These data suggest that SREBP-1 positively contributes to A-II-induced cardiac injury partly via the involvement of slowly progressed inflammation, which may be induced by the attenuated responses of antioxidant gene program.
- © 2011 by American Heart Association, Inc.