AT1-receptor-deficiency induced atheroprotection in diabetic mice is partially mediated via PPARγ.

Objective: Peroxisome-proliferator-activated-receptor-γ (PPARγ) acts as a transcriptional regulator of multiple genes involved in glucose and lipid metabolism. In vitro studies showed that activated PPARγ suppresses AT1R-gene expression and vice versa. However, it has not yet been determined in vivo, whether AT1R-PPARγ-interactions play a relevant role in the pathogenesis of diabetic complications and specifically in accelerated atherosclerosis.

Stimulation of the AT2 receptor reduced atherogenesis in ApoE(-/-)/AT1A(-/-) double knock out mice.

AT1 receptor blockers (ARB) and in part ACE inhibitors (ACI) potentially exert beneficial effects on atherogenesis independent of AT1 receptor inhibition. These pleiotropic effects might be related to angiotensin II mediated activation of the AT2 receptor. To analyze this hypothesis we investigated the development of atherosclerosis and the role of ACIs and ARBs in apolipoprotein E-deficient (ApoE(-/-)) mice and in ApoE/AT1A receptor double knockout mice (ApoE(-/-)/AT1A(-/-)).

Inhibition of leukotriene C4 action reduces oxidative stress and apoptosis in cardiomyocytes and impedes remodeling after myocardial injury.

Unlabelled: Tissue damage leads to release of pro-inflammatory mediators. Among these, leukotriene C(4) (LTC(4)) is a powerful, intracellularly induced mediator of inflammation, which requires inside-out transport of LTC(4). We investigated whether release of LTC(4)via the multidrug resistance related protein 1 (MRP1) induces apoptosis in cardiomyocytes in vitro and in vivo.

Role of the multidrug resistance protein-1 (MRP1) for endothelial progenitor cell function and survival.

The multidrug resistance related protein-1 (MRP1) is a member of the ATP binding cassette (ABC) of cell surface transport proteins expressed in multiple cell lines and tissues including endothelial cells and haematopoietic stem cells. MRP1 blockade has been shown to prevent endothelial cell apoptosis and improve endothelial function. Besides mature endothelial cells vascular homing of endothelial progenitor cells (EPC) contributes to endothelial regeneration after vascular damage.

Angiotensin II triggers release of leukotriene C4 in vascular smooth muscle cells via the multidrug resistance-related protein 1.

The multidrug resistance-related protein-1 (MRP1) is important for the management of oxidative stress in vascular cells in vivo. Substrates of MRP1 are, among others, glutathione and the leukotriene C(4) (LTC(4)), an eicosanoid and mediator of inflammation. Angiotensin (Ang) II infusion results in MRP1(-/-) mice compared to wild-type mice in improved endothelial function and reduced reactive oxygen species (ROS) formation.

Interaction of Inhibitor of DNA binding 3 (Id3) with Gut-enriched Krüppel-like factor (GKLF) and p53 regulates proliferation of vascular smooth muscle cells.

Enhanced proliferation of vascular smooth muscle cells (VSMCs) is one of the key features of the pathogenesis of atherosclerosis. The helix-loop-helix protein Inhibitor of DNA binding 3 (Id3) contributes to regulation of VSMC proliferation in a redox-sensitive manner. We investigated the role of Id3 and its interaction with other redox-sensitive genes, the transcription factor Gut-enriched Krüppel-like factor (GKLF, KLF4) and the tumor suppressor gene p53 in the regulation of VSMC proliferation.

The heterogenous nuclear riboprotein S1-1 regulates AT1 receptor gene expression via transcriptional and posttranscriptional mechanisms.

The AT1 receptor plays an essential role in the pathogenesis of atherosclerosis. AT1 receptor expression is predominately mediated via mRNA destabilization by mRNA binding proteins. We identified via MALDI-analysis the heterogenous nuclear riboprotein S1-1 as an important regulator of AT1 receptor mRNA stability.

Multidrug resistance protein-1 affects oxidative stress, endothelial dysfunction, and atherogenesis via leukotriene C4 export.

Background: We recently showed that the multidrug resistance related protein-1 (MRP1) is important for the management of oxidative stress in vascular cells. However, the underlying mechanism and the in vivo relevance of these findings remain elusive. We hypothesize that inside-outside transport of leukotriene C(4) (LTC(4)) via MRP1 is a substantial proatherogenic mechanism in the vasculature.

Differential phosphorylation of calreticulin affects AT1 receptor mRNA stability in VSMC.

The AT1 receptor plays a pivotal role for the pathogenesis of hypertension and atherosclerosis. AT1 receptor expression is regulated posttranscriptionally via destabilization of the AT1 receptor mRNA by mRNA binding proteins. Recently, we identified calreticulin as a novel binding protein within the 3'untranslated region of the AT1 receptor mRNA.

Role of the multidrug resistance protein-1 in hypertension and vascular dysfunction caused by angiotensin II.

Objective: Human endothelial cells use the multidrug resistance protein-1 (MRP1) to export glutathione disulfide (GSSG). This can promotes thiol loss during states of increased glutathione oxidation. We investigated how MRP1 modulates blood pressure and vascular function during angiotensin II-induced hypertension.

The role of the multidrug resistance protein-1 in modulation of endothelial cell oxidative stress.

Glutathione (GSH) is the major source of intracellular sulfhydryl groups. Oxidized GSH (GSSG) can be recycled to GSH by the GSH reductase or exported from the cell. The mechanism by which GSSG is exported and the consequence of its export from endothelial cells has not been defined previously.

ATVB in focus: redox mechanisms in blood vessels.

Reactive oxygen species have been implicated in the pathogenesis of virtually every stage of vascular lesion formation, hypertension, and other vascular diseases. We are currently gaining insight into important sources of reactive oxygen species in the vessel wall, including the NADPH oxidases, xanthine oxidase, uncoupled nitric oxide synthase, and mitochondrial sources. Although various reactive oxygen species have pathological roles, some serve as important signaling molecules that modulate vascular tone, growth, and remodeling.