The abstract below was mistakenly withdrawn from the Circulation Scientific Sessions 2001 abstracts supplement.
Specialty/Subspecialty: Basic Science/Signal Transduction/Receptors/Growth
Differential Regulation of E2F Family Members During Normal Cardiac Development and Myocyte Hypertrophy
Dharmesh Vara, Katrina Bicknell, Univ of Reading, Reading UK; Nick La Thangue, Prolifix Ltd, Oxon UK; Gavin Brooks, Univ of Reading, Reading UK
E2F comprises a family of at least 6 transcription factors that control the G1/S transition in mammalian cells. It previously has been reported that E2F expression is down regulated during cardiac development; however, it remains unclear whether all E2F family members are expressed in developing cardiac tissue or whether they all show this pattern of down-regulation. In addition, a role for E2F in cardiac hypertrophy remains to be determined. We have investigated the mRNA and protein expressions of E2F 1, 2, 3, 4, 5, DP-1 and DP-2, during normal rat cardiac development and during the development of hypertrophy in cultured myocytes. Our results show that during development, protein levels of E2F 1 - 4, DP-1 and DP-2 are down-regulated from E18 to adult (2.5, 3, 1.5, 3.5, 3 and 2.5-fold, respectively). In contrast, E2F 5 is up-regulated 9-fold. Induction of hypertrophy in cultured 3d-old neonatal rat myocytes (20% FCS, 24 hrs) led to a significant up-regulation of E2F 1 - 4 and DP-1 (2.5, 0.5, 3.0, 2-fold, respectively), and down-regulation of E2F-5 (5.6-fold), compared to control cultures (0% FCS). Induction of hypertrophy was confirmed by measuring atrial (ANF) and brain (BNP) natriuretic factor/peptide mRNA levels, that both increased 3-fold, and total protein levels that doubled in hypertrophied myocytes compared to controls. Interestingly, E2F-mediated cyclin E promoter luciferase activity increased 2-fold in myocytes undergoing hypertrophy compared with controls and using a peptide (AH2, 30μM) that blocks E2F:DP heterodimerisation and abolishes E2F function, we showed that ANF and BNP mRNA expressions were reduced dramatically compared with control cells whereas expression of the house-keeping gene, GAPDH, was unaltered. A control peptide was without effect. In addition, AH2 abrogated completely protein synthesis in myocytes stimulated to undergo hypertrophy whereas the control peptide had no effect. Our results suggest that down-regulation of certain E2F family members might play a role in terminal differentiation of the heart. Interestingly, inhibiting E2F expression and activity during the development of hypertrophy abrogates adaptive hypertrophic growth and thus might be a potential therapeutic target for the treatment of heart failure.
In abstract No. 1764, “Does Vitamin C Improve Endothelial Function in Patients with Coronary Artery Disease and Diabetes Mellitus?,” which appeared in the Scientific Sessions 2001 abstracts supplement (Circulation. 2001;104(suppl II):II-370), Dr Stefanadis’ name was spelled incorrectly. The corrected abstract appears below.
Does Vitamin C Improve Endothelial Function in Patients with Coronary Artery Disease and Diabetes Mellitus?
Charalambos Antoniades, Dimitrios Tousoulis, Costa Tentolouris, Kyriakoula Marinou, Georgios Goumas, Christodoulos Stefanadis, Athens Univ Med Sch, Athens Greece
Background. Coronary artery disease (CAD) as well as diabetes mellitus (DM), are both known to be associated with endothelial dysfunction. Oxidative stress is considered to be one of the most important mechanisms involved in the pathogenesis of endothelial dysfunction in CAD and DM. In this study we investigated the hypothesis that treatment with the antioxidant vitamin C improves endothelial function in patients with type I or II DM and CAD. Methods. In a double-blind placebo-controlled study, 44 patients (41 males, 3 females, aged 67+/-1.4 years) with CAD and DM, were enrolled. 18 of them were of type I DM and 26 of type II. 16 diabetic patients (5 with type I DM (group A) and 11 with type II DM (group B)) were treated with vitamin C 2g/day for 4 weeks. The rest of them (13 with type I DM (group C) and 15 with type II DM (group D)) received placebo for 4 weeks. Forearm blood flow was measured using venous occlusion strain-gauge plethysmography, at baseline and after treatment. Åndothelium dependent vasodilation was expressed as the % change from baseline to post reactive hyperemia blood flow (RH%). Endothelium independent flow (NTG%) was assessed as the % change from baseline to post sublingual nitroglycerin administration flow. Results. Basal blood pressure, heart rate, body weight, basal forearm blood flow and endothelium independent flow remained unchanged in all groups. All values are expressed as mean+/-SEM. RH% was approximately the same between patients with type I (55.9+/-6.3%) and type II (57.8+/-6.0%, p=NS) DM. After treatment, RH% was significantly increased in group A (from 56.8+/-12.3 to 72.6+/-9.7% p<0.05) and B (from 66,5+/-11.7 to 84.3+/-15.1% p<0.05) while remained unchanged in groups C (from 53.8+/-9.6 to 51.3+/-10.2% p=NS) and D (from 55,8+/-11,6 to 58,3+/-10,1% p=NS). Conclusions. Chronic administration of vitamin C seems to improve endothelial function in patients with combined coronary artery disease and diabetes mellitus of type I or II.