Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may exert pleiotropic effects on vascular cells independent of lowering plasma cholesterol. To elucidate the molecular mechanisms involved in these effects, we investigated the impact of statins on production of reactive oxygen species (ROS) in rat aortic vascular smooth muscle cells (VSMC). Exposure of VSMC to angiotensin II caused production of ROS via angiotensin AT1 receptor activation. Pretreatment with atorvastatin inhibited angiotensin II-induced ROS production. Atorvastatin decreased AT1 receptor mRNA levels in a time- and concentration-dependent manner and consistently reduced AT1 receptor density. L-Mevalonate but not hydroxy-cholesterol reversed the inhibitory effect of atorvastatin on AT1 receptor transcript levels. Inhibition of geranylgeranyl-transferase but not of farnesyl-transferase mimicked the effect of atorvastatin on AT1 receptor gene expression. Atorvastatin did not decrease AT1 receptor gene transcription but did reduce the half-life of the AT1 receptor mRNA. AT1 receptor activation by angiotensin II increased the expression of the GTPase rac1, enhanced rac1 GTP-binding activity, and increased the geranylgeranyl-dependent translocation of rac1 to the cell membrane. In contrast, statins inhibited rac1 activity and membrane translocation. Consequently, specific inhibition of rac1 with Clostridium sordellii lethal toxin blocked angiotensin II-induced production of free radicals. Finally, treatment of rats with atorvastatin caused down-regulation of aortic AT1 receptor mRNA expression and reduced aortic superoxide production in vivo. Cholesterol-independent down-regulation of AT1 receptor gene expression and inhibition of rac1, leading to decreased ROS production, demonstrates a novel regulatory mechanism of statins that may contribute to the beneficial effects of these drugs beyond lowering of plasma cholesterol.
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PMID:Inhibition of geranylgeranylation reduces angiotensin II-mediated free radical production in vascular smooth muscle cells: involvement of angiotensin AT1 receptor expression and Rac1 GTPase. 1117 61

It is proposed that AT1 antagonists (ARBs) exert their biological action by inserting into the lipid membrane and then diffuse to the active site of AT1 receptor. Thus, lipid bilayers are expected to be actively involved and play a critical role in drug action. For this reason, the thermal, dynamic and structural effects of olmesartan alone and together with cholesterol were studied using differential scanning calorimetry (DSC), 13C magic-angle spinning (MAS) nuclear magnetic resonance (NMR), cross-polarization (CP) MAS NMR, and Raman spectroscopy as well as small- and wide angle X-ray scattering (SAXS and WAXS) on dipalmitoyl-phosphatidylcholine (DPPC) multilamellar vesicles. 13C CP/MAS spectra provided direct evidence for the incorporation of olmesartan and cholesterol in lipid bilayers. Raman and X-ray data revealed how both molecules modify the bilayer's properties. Olmesartan locates itself at the head-group region and upper segment of the lipid bilayers as 13C CP/MAS spectra show that its presence causes significant chemical shift changes mainly in the A ring of the steroidal part of cholesterol. The influence of olmesartan on DPPC/cholesterol bilayers is less pronounced. Although, olmesartan and cholesterol are residing at the same region of the lipid bilayers, due to their different sizes, display distinct impacts on the bilayer's properties. Cholesterol broadens significantly the main transition, abolishes the pre-transition, and decreases the membrane fluidity above the main transition. Olmesartan is the only so far studied ARB that increases the gauche:trans ratio in the liquid crystalline phase. These significant differences of olmesartan may in part explain its distinct pharmacological profile.
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PMID:Thermal, dynamic and structural properties of drug AT1 antagonist olmesartan in lipid bilayers. 2184 1