Abstract 702: Angiotensin Converting Enzyme (ACE) Inhibitors Modulate Gene Expression in Human Endothelial Cells and Adipocytes via the ACE-Dependent Signaling
ACE inhibitors (ACEI) exert beneficial effects on cardiovascular homeostasis and delay the onset of type 2 diabetes (T2D). We have previously shown that ACE is a signal transduction molecule, activated after binding of an ACEI and that the ACE signaling is dependent on the phosphorylation of ACE on Ser1270. Since the JNK/cJun pathway and the transcription factor AP-1 are part of the ACE signaling cascade, we analysed gene expression in response to ACEI. We identified (DNA microarray) 21 genes that were 4-fold up- or downregulated by ramiprilat (100 nmol/L) in human endothelial cells expressing wild-type ACE but not in cells expressing a nonphosphorylatable, signaling-dead ACE mutant (S1270A). One of the 7 genes upregulated by the ACEI was the cellular retinol-binding protein 1 (CRBP1), which belongs to the family of fatty acid binding proteins and might play a role during development of insulin resistance. In vivo analysis confirmed that the treatment with ACEI significantly enhanced the plasma level of CRBP1 in patients with T2D or coronary artery disease (CAD). Similar effects were found on plasma levels of retinol binding protein 4. Since both proteins are retinol-transport proteins and potentially influence nuclear receptor proteins (RAR/RXR), which are abundant in adipose tissue and regulate adipocyte gene expression together with peroxisome proliferator-activated receptors (PPAR), we determined the effect of ACEI on adipokine expression. Circulating levels of adiponectin were markedly lower in patients with T2D or CAD than in healthy individuals. However, treatment with an ACEI (5mg/d) restored adiponectin levels up to that of healthy controls, a response that was similar to that obtained with the PPARγ-agonist rosiglitazone. Moreover, in isolated human visceral adipocytes ACEI and rosiglitazone increased lipid storage to a similar extent, and the former was prevented by PPARγ antagonism or JNK inhibition. These data indicate that ACEI affect adipocyte homeostasis, most probably through activation of RAR/RXR-PPARγ signaling. Enhanced plasma levels of the anti-inflammatory and anti-atherogenic adipokine adiponectin together with increased adipocyte lipid storage may contribute to the beneficial effects of ACEI on the development of T2D.