Epoxyeicosatrienoic acid agonist rescues the metabolic syndrome phenotype of HO-2-null mice.
Komal Sodhi,Kazuyoshi Inoue,Katherine H. Gotlinger,Martina Canestraro,Luca Vanella,Dong Hyun Kim,Vijay L. Manthati,Sreenivasulu Reddy Koduru,John R. Falck,Michal L. Schwartzman,Nader G. Abraham +10 more
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TLDR
The decrease in cyp2c expression and EETs levels in HO-2-null mice underscores the importance of the HO system in the regulation of epoxygenase levels and suggests that protection against obesity-induced cardiovascular complications requires interplay between these two systems.Abstract:
Heme oxygenase (HO) and cytochrome P450 (P450)-derived epoxyeicosatrienoic acids (EETs) participate in vascular protection, and recent studies suggest these two systems are functionally linked. We examined the consequences of HO deficiency on P450-derived EETs with regard to body weight, adiposity, insulin resistance, blood pressure, and vascular function in HO-2-null mice. The HO-2-null mice were obese, displayed insulin resistance, and had high blood pressure. HO-2 deficiency was associated with decreases in cyp2c expression, EET levels, HO-1 expression, and HO activity and with an increase in superoxide production and an impairment in the relaxing response to acetylcholine. In addition, HO-2-null mice exhibited increases in serum levels of tumor necrosis factor (TNF)-α and macrophage chemoattractant protein (MCP)-1 and a decrease in serum adiponectin levels. Treatment of HO-2-null mice with a dual-activity EET agonist/soluble epoxide hydrolase inhibitor increased renal and vascular EET levels and HO-1 expression, lowered blood pressure, prevented body weight gain, increased insulin sensitivity, reduced subcutaneous and visceral fat, and decreased serum TNF-α and MCP-1, while increasing adiponectin and restoring the relaxing responses to acetylcholine. The decrease in cyp2c expression and EETs levels in HO-2-null mice underscores the importance of the HO system in the regulation of epoxygenase levels and suggests that protection against obesity-induced cardiovascular complications requires interplay between these two systems. A deficiency in one of these protective systems may contribute to the adverse manifestations associated with the clinical progression of the metabolic syndrome.read more
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Journal ArticleDOI
Impact of Soluble Epoxide Hydrolase and Epoxyeicosanoids on Human Health
TL;DR: How the pharmacological stabilization of EETs and other natural epoxy-fatty acids could lead to possible disease therapies is discussed.
Journal ArticleDOI
Epoxides and Soluble Epoxide Hydrolase in Cardiovascular Physiology
TL;DR: There is emerging evidence that development of EET-based therapeutics will be beneficial for cardiovascular diseases and pharmacological and genetic manipulations of Eets and sEH have demonstrated a contribution for this metabolic pathway to cardiovascular diseases.
Journal ArticleDOI
Salt Sensitivity of Blood Pressure
Fernando Elijovich,Myron H. Weinberger,Cheryl A.M. Anderson,Lawrence J. Appel,Michael Bursztyn,Nancy R. Cook,Richard A. Dart,Christopher Newton-Cheh,Frank M. Sacks,Cheryl L. Laffer +9 more
TL;DR: Understanding of its pivotal mechanisms may lead to specific therapies to decrease the cardiovascular risk associated with this trait in humans, and identification of biochemical or genetic markers of salt-sensitivity for use in the clinic would improve risk stratification of hypertensive and prehypertensive subjects.
Journal ArticleDOI
Salt Sensitivity of Blood Pressure: A Scientific Statement From the American Heart Association.
Fernando Elijovich,Myron H. Weinberger,Cheryl A.M. Anderson,Lawrence J. Appel,Michael Bursztyn,Nancy R. Cook,Richard A. Dart,Christopher Newton-Cheh,Frank M. Sacks,Cheryl L. Laffer +9 more
TL;DR: The simplest definition of salt sensitivity of blood pressure (SSBP) states that it is a physiological trait present in rodents and other mammals, including humans, by which the blood pressure of some members of the population exhibits changes parallel to changes in salt intake as discussed by the authors.
Journal ArticleDOI
Heme Oxygenase in the Regulation of Vascular Biology: From Molecular Mechanisms to Therapeutic Opportunities
Young-Myeong Kim,Hyun-Ock Pae,Jeong Euy Park,Yong Chul Lee,Je Moon Woo,Nam-Ho Kim,Yoon Kyung Choi,Bok-Soo Lee,So Ri Kim,Hun-Taeg Chung +9 more
TL;DR: The rationale for exploring the potential therapeutic role for HO system in the amelioration of vascular inflammation and prevention of adverse cardiovascular outcomes is provided.
References
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P-450 Metabolites of Arachidonic Acid in the Control of Cardiovascular Function
TL;DR: It is likely that CYP metabolites of arachidonic acid contribute to the changes in renal function and vascular tone associated with some of these conditions and that drugs that modify the formation and/or actions of EETs and 20-HETE may have therapeutic benefits.
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Nader G. Abraham,Attallah Kappas +1 more
TL;DR: The use of pharmacological and genetic probes to manipulate HO, leading to new insights into the complex relationship of the HO system with biological and pathological phenomena under investigation, is reviewed.
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TL;DR: Both in vivo and in vitro, activation of AMPK was the first effect of gACRP30 and was transient, whereas alterations in malonyl CoA and ACC occurred later and were more sustained, indicating that gAC RP30 most likely exerts its actions on muscle fatty acid oxidation by inactivating ACC via activation ofAMPK and perhaps other signal transduction proteins.
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The Kidney, Hypertension, and Obesity
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Adiponectin Stimulates Angiogenesis by Promoting Cross-talk between AMP-activated Protein Kinase and Akt Signaling in Endothelial Cells
Noriyuki Ouchi,Hideki Kobayashi,Shinji Kihara,Masahiro Kumada,Kaori Sato,Tatsuya Inoue,Tohru Funahashi,Kenneth Walsh +7 more
TL;DR: Data indicate that adiponectin can function to stimulate the new blood vessel growth by promoting cross-talk between AMP-activated protein kinase and Akt signaling within endothelial cells.
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