Estradiol-Mediated Endothelial Nitric Oxide Synthase Association With Heat Shock Protein 90 Requires Adenosine Monophosphate-Dependent Protein Kinase

Schulz, Eberhard; Anter, Elad; Zou, Ming; Keaney, John F.

doi:10.1161/circulationaha.105.546812

Cited by 97 publications

(99 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the increase of the AMPK activation state induced by 17-estradiol treatment seems to be sufficient to phosphorylate HMGR and to restore its proper activity. The enhancement of estradiol-induced AMPK activation is supported also by other data in the literature (Schulz et al, 2005). …”

Section: Discussionsupporting

confidence: 84%

Hypercholesterolemia and 3-hydroxy-3-methylglutaryl coenzyme A reductase regulation in aged female rats

Trapani¹,

Violo²,

Pallottini³

2010

Experimental Gerontology

View full text Add to dashboard Cite

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT ACCEPTED MANUSCRIPT 2 AbstractCoronary heart disease is less prevalent in pre-menopausal women than in men, but increases at the onset of menopause. This delay is due to estrogen protective effects. The rise of cholesterolemia is one of the main risk factors for coronary disease. Since 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) is the rate-limiting enzyme of the cholesterol biosynthetic pathway, it plays a pivotal role in cholesterol homeostasis maintenance. Aim of this study is to investigate whether HMGR is involved in the cholesterolemia increase that occurs during aging, and to consider its potential role as a target for estrogen protective effects. "In vivo" studies have been performed using the livers of 12-month-old female rats (whose estrogen level decrease is comparable to the one detected at the occurrence of human estropause), 12-month-old female rats treated with 17--estradiol, and 3-month-old untreated male and female rats. The results indicated hypercholesterolemic status and a significant increase of HMGR activity according to a reduced activation of AMPK detected in treated rats compared to controls. Furthermore, 17-estradiol treatment reduced HMGR activity restoring AMPK activation. These findings highlight the correlation between estrogen and HMGR short-term regulation, and suggest the presence of another mechanism underlying the protective role of estrogen in age-related diseases.

show abstract

Section: Discussionsupporting

confidence: 84%

Hypercholesterolemia and 3-hydroxy-3-methylglutaryl coenzyme A reductase regulation in aged female rats

Trapani¹,

Violo²,

Pallottini³

2010

Experimental Gerontology

View full text Add to dashboard Cite

show abstract

“…As AMPK is quite sensitive to changes in the AMP/ATP ratio, this effectively reduces AMPK activation. 39 In our studies, we found that pre-treatment with either Ara-A or 59-iodotubercidin inhibited AMPK phosphorylation as determined by western blot analysis following EGCG treatment (Figure 6a). Although both inhibitors prevented AMPK phosphorylation, iNOS protein expression, supernatant NO levels and IL-6 production were still inhibited following EGCG treatment (Figure 6b-d).…”

Section: Egcg Inhibits Inflammation In Lupus Mesangial Cellsmentioning

confidence: 55%

Epigallocatechin-3-gallate (EGCG) attenuates inflammation in MRL/lpr mouse mesangial cells

et al. 2010

View full text Add to dashboard Cite

Epigallocatechin-3-gallate (EGCG), a bioactive component of green tea, has been reported to exert anti-inflammatory effects on immune cells. EGCG is also shown to activate the metabolic regulator, adenosine 5'-monophosphate-activated protein kinase (AMPK). Reports have also indicated that EGCG inhibits the immune-stimulated phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. The PI3K/Akt/mTOR pathway has been implicated in mesangial cell activation in lupus. Mesangial cells from MRL/lpr lupus-like mice are hyper-responsive to immune stimulation and overproduce nitric oxide (NO) and other inflammatory mediators when stimulated. In our current studies, we sought to determine the mechanism by which EGCG attenuates immune-induced expression of pro-inflammatory mediators. Cultured mesangial cells from MRL/lpr mice were pre-treated with various concentrations of EGCG and stimulated with lipopolysaccharide (LPS)/interferon (IFN)-c. EGCG activated AMPK and blocked LPS/ IFN-c-induced inflammatory mediator production (iNOS expression, supernatant NO and interleukin-6). Interestingly, EGCG attenuated inflammation during AMPK inhibition indicating that the anti-inflammatory effect of EGCG may be partially independent of AMPK activation. Furthermore, we found that EGCG effectively inhibited the immune-stimulated PI3K/Akt/mTOR pathway independently of AMPK, by decreasing phosphorylation of Akt, suggesting an alternate mechanism for EGCG-mediated anti-inflammatory action in mesangial cells. Taken together, these studies show that EGCG attenuated inflammation in MRL/lpr mouse mesangial cells via the PI3K/Akt/mTOR pathway. Our findings suggest a potential therapeutic role for the use of EGCG to regulate inflammation and control autoimmune disease.

show abstract

“…This temporal response is similar to that stimulated by shear stress, by adiponectin and by metformin. [25][26][27][28] Sun et al 13 showed that the phosphorylation/ activation of AMPK in mouse aorta and myocardium was observed as early as 2 h and peaked at 4-8 h after atrovastatin administration. However, the role of AMPK in angiogenesis in vivo has not been fully elucidated.…”

Section: Discussionmentioning

confidence: 99%

Pravastatin accelerates ischemia-induced angiogenesis through AMP-activated protein kinase

et al. 2009

View full text Add to dashboard Cite

Statins exert pleiotropic effects on the cardiovascular system, in part through an increase in nitric oxide (NO) bioavailability. In this study, we examined the role of pravastatin in ischemia-induced angiogenesis. Unilateral hindlimb ischemia was surgically induced in C57BL/6J mice. Phosphorylation of AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC) and endothelial NO synthase (eNOS) was increased in ischemic tissues. Furthermore, mice treated with pravastatin showed higher increases in phosphorylation than did untreated mice. Laser Doppler analysis has shown that pravastatin treatment accelerates the development of collateral vessels and angiogenesis in response to hindlimb ischemia. Capillary density in the ischemic hindlimb was also increased by pravastatin treatment. An in vitro study on human umbilical vein endothelial cells (HUVECs) revealed that pravastatin increased the phosphorylation of AMPK. Pravastatin-induced phosphorylation of eNOS, one of the downstreams of AMPK, was inhibited by compound C, an AMPK antagonist. The increased migration and tube formation of HUVECs by pravastatin were significantly blocked by compound C treatment. The accelerated angiogenesis by pravastatin after hindlimb ischemia was significantly reduced after treatment with compound C. Thus, ischemia induced AMPK phosphorylation in vivo. Furthermore, pravastatin could also activate AMPK in vivo and in vitro. Such phosphorylation results in eNOS activation and angiogenesis, which provide a novel explanation for one of the pleiotropic effects of statins that is beneficial for angiogenesis. Keywords: angiogenesis; endothelium; ischemia; nitric oxide synthase; statins INTRODUCTIONThe AMP-activated protein kinase (AMPK) is a trimeric enzyme comprising a catalytic a-subunit and regulatory-b, g-subunits. AMPK was identified as an upstream kinase that phosphorylates and hence inactivates 3-hydroxy-3-methylglutaryl-coenzyme A reductase and acetyl-coenzyme A carboxylase (ACC), key enzymes that control choresterol/isoprenoid and fatty acid biosynthesis, respectively. AMPK is considered to be a cellular energy sensor that stimulates ATP-producing catabolic pathways and inhibits ATP-consuming anabolic pathways. 1 Thus, the AMPK pathway is thought to be a regulator of stress responses and cellular energy homeostasis. However, recent studies have shown that AMPK also plays an important role in maintaining endothelial functions. 2 AMPK activation has beneficial effects on endothelial functions and in antiatherogenesis. These effects include the induction of the endothelial nitric oxide synthase (eNOS) pathway to increase NO bioavailability; the suppression of endothelial reactive oxygen species production when stimulated by hyperglycemia or high free fatty acids to improve endothelial free fatty acid oxidation and limit lipid accumulation; the inhibition of apoptosis and inflammation; and the modulation of the vascular tone. 3,4

show abstract

Estradiol-Mediated Endothelial Nitric Oxide Synthase Association With Heat Shock Protein 90 Requires Adenosine Monophosphate-Dependent Protein Kinase

Cited by 97 publications

References 46 publications

Hypercholesterolemia and 3-hydroxy-3-methylglutaryl coenzyme A reductase regulation in aged female rats

Hypercholesterolemia and 3-hydroxy-3-methylglutaryl coenzyme A reductase regulation in aged female rats

Epigallocatechin-3-gallate (EGCG) attenuates inflammation in MRL/lpr mouse mesangial cells

Pravastatin accelerates ischemia-induced angiogenesis through AMP-activated protein kinase

Contact Info

Product

Resources

About