Related Experiment Videos
Methotrexate in atherogenesis and cholesterol metabolism
Eric Coomes1, Edwin S L Chan, Allison B Reiss
1Department of Medicine, Division of Translational Medicine, New York University School of Medicine, NBV 16N1, 550 First Avenue, New York, NY 10016, USA.
Cholesterol
|April 15, 2011
Summary
Methotrexate benefits cardiovascular health by upregulating cholesterol transporters, while COX-2 inhibitors harm it. Understanding these effects on cholesterol homeostasis aids in developing new anti-inflammatory heart medications.
Area of Science:
- Pharmacology
- Cardiovascular Medicine
- Molecular Biology
Background:
- Rheumatoid arthritis (RA) is linked to increased cardiovascular risk.
- Anti-inflammatory drugs can impact cardiovascular health through various mechanisms.
- Opposing cardiovascular effects of methotrexate and COX-2 inhibitors suggest differential impacts on cholesterol homeostasis.
Purpose of the Study:
- To investigate the opposing cardiovascular effects of methotrexate and COX-2 inhibition.
- To elucidate the mechanisms by which these drugs affect cholesterol homeostasis proteins.
- To identify potential targets for novel cardioprotective anti-inflammatory drugs.
Main Methods:
- Examined the effects of methotrexate and COX-2 inhibition on ATP-binding cassette transporter (ABC) A1 and cholesterol 27-hydroxylase expression.
- Investigated the role of adenosine signaling pathways, including A(2A) and A(3) receptors, cAMP-PKA-CREB, and STAT inhibition.
- Analyzed the impact on cellular cholesterol efflux and reverse cholesterol transport.
Main Results:
- Methotrexate upregulates cholesterol 27-hydroxylase and ABCA1 expression via adenosine release.
- COX-2 inhibition downregulates these key cholesterol homeostasis proteins.
- Adenosine signaling through A(2A) and A(3) receptors influences proteins involved in reverse cholesterol transport.
Conclusions:
- Differential effects on cholesterol homeostasis proteins explain the opposing cardiovascular impacts of methotrexate and COX-2 inhibitors.
- Adenosine-mediated pathways are crucial in regulating reverse cholesterol transport.
- Selective A(2A) receptor agonists represent a promising strategy for developing cardioprotective anti-inflammatory therapies.
Related Concept Videos
01:11Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase
Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
01:29Therapeutic Drug Monitoring: Affecting Factors
Therapeutic Drug Monitoring (TDM) is the clinical practice of measuring specific drug levels in a patient's blood or body tissues to manage and optimize therapy. TDM is crucial for drugs with narrow therapeutic windows, like warfarin and phenytoin, where incorrect doses can lead to treatment failure or severe side effects. This monitoring ensures the dosage administered is within a safe and effective range. The factors affecting therapeutic drug monitoring include:Patient-Specific Factors:a.
01:20Lipid-Lowering Drugs: Statins and Miscellaneous Agents
Hyperlipidemia, a medical condition often referred to as high cholesterol, is characterized by abnormally elevated levels of lipids in the bloodstream. When present in excess, these lipids, specifically cholesterol and triglycerides, can lead to serious health complications, often involving cardiovascular diseases. Illnesses like atherosclerosis, heart attacks, and pancreatitis have all been linked to untreated hyperlipidemia. This means controlling and regulating cholesterol and triglyceride...
01:26Atherosclerosis III: Management
Management of atherosclerosis involves an integrated strategy encompassing pharmacological treatment, surgical interventions, lifestyle changes, and nutrition therapy to address the multifactorial nature of the disease.Pharmacological TherapyA cornerstone of atherosclerosis management is the use of pharmacological agents. Statins, such as atorvastatin, are pivotal in inhibiting HMG-CoA reductase, an enzyme that catalyzes an initial step in cholesterol synthesis in the liver. This reduction in...
01:29Drugs for Treatment of Crohn's Disease in IBD Using Immunomodulatory Agents
Crohn's disease is an inflammatory bowel disorder marked by chronic inflammation of the GI tract. Various treatment strategies for Crohn's disease are employed, such as immunomodulatory agents, glucocorticoids, and biologics or anti-TNF therapy. Azathioprine (Imuran), a commonly used immunomodulatory drug for Crohn's disease, is converted in the body to mercaptopurine, which inhibits purine biosynthesis and cell proliferation. Both are utilized in severe cases of Inflammatory Bowel Disease...
01:29Cholesterol: Significance and Regulation
Although not a source of energy, cholesterol plays a significant role as a foundational structure for bile salts, steroid hormones, and vitamin D, as well as being a crucial component of plasma membranes. Approximately 15% of blood cholesterol is derived from our diet, with the remainder synthesized from acetyl CoA by the liver and intestines. Cholesterol is eliminated from the body through its conversion into bile salts, which are eventually discarded in the feces.
Considering cholesterol and...
Considering cholesterol and...