Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

UCSD researchers identify new role for drugs in prevention, treatment of atherosclerosis

02.12.2004


Drugs that work in the liver to reduce fatty triglyceride levels and improve insulin resistance, are also effective at inhibiting the formation of cholesterol-laden plaques that cause atherosclerosis in artery walls, according to researchers at the University of California, San Diego (UCSD) School of Medicine.



In studies with mice published in the Dec. 1, 2004 issue of the Journal of Clinical Investigation, the researchers found that drugs that activate two types of proteins called peroxisome proliferators-activated receptors (PPARs), specifically PPAR-gamma and PPAR-alpha, have a direct effect in the artery wall that prevents the accumulation of cholesterol in atherosclerotic lesions by up to 70 percent, as compared to untreated mice fed a high cholesterol diet. The scientists also determined the molecular pathways taken by the two versions of the PPAR drugs, a finding that could potentially be used to develop new anti-atherosclerotic medications.

"While current preventative therapy for cardiovascular disease is primarily based on reducing global risk factors such as hypertension, cholesterol levels and smoking, these findings provide a potential new strategy for the prevention and treatment of atherosclerosis," said the study’s co-senior author, Christopher Glass, M.D., Ph.D., UCSD professor of Cellular and Molecular Medicine. "We’ve shown that drugs that activate PPAR-gamma and PPAR-alpha will not only reduce triglyceride levels and improve insulin levels, as previously known, but will also inhibit key processes in the artery wall that are directly responsible for the development of atherosclerosis."


Nearly 5 million Americans have atherosclerosis, which is the deposit of fatty substances, cholesterol and waste materials on the innermost layer of the walls of large and medium-sized arteries. These plaques, as they are called, can grow significantly large enough to restrict blood flow and cause a heart attack.

The UCSD team focused their study on the three subtypes of PPAR – alpha, gamma and beta/delta – in mice fed a high cholesterol diet. Although the UCSD scientists and others demonstrated in the past that PPAR-gamma drugs such as Rosiglitazone inhibit the development of atherosclerosis in mice, they did not know, until now, the cascade of molecular events that accomplished this in the living body.

The new study in mice also demonstrated that PPAR-alpha drugs that are similar to Gemfibrizol (used to lower triglyceride levels), but much more potent, were effective as an anti-atherosclerotic medication. Reductions in atherosclerosis ranged from 50 to 70 percent, depending upon the location within the arteries. This effect was similar to the 40 to 70 percent reductions previously observed for PPAR-gamma drugs under similar experimental conditions.

On the other hand, PPAR-beta/delta agents failed to inhibit atherosclerosis with the results not significantly different from those of control animals receiving non-active drugs.

While the three PPARs are very similar proteins and are expressed in all major cell types that make up atherosclerotic lesions, including immune system macrophages, smooth muscle cells, lymphocytes and endothelial cells, the researchers unexpectedly found that PPAR-alpha and PPAR-gamma drugs worked to inhibit atherosclerosis through different molecular pathways. PPAR-alpha worked in the artery wall by regulating the genes involved in the transport and metabolic breakdown of cholesterol, called LXRs. In contrast, the ability of PPAR-gamma to inhibit atherosclerosis was independent of LXR and, instead, induced expression of another protein called ATP-binding cassette G1 (ABCG1) in macrophages and artery walls. ABCG1 has recently been shown by other investigators to transfer cholesterol from cells to high density lipoproteins (HDL), the carrier of so-called "good cholesterol" in the blood. The discovery that this transport process is stimulated by Rosiglitazone provides an important clue as to how PPAR-gamma might prevent the accumulation of cholesterol in the artery wall.

"These findings define distinct biological roles for the PPAR subunits," said the paper’s co-senior author Wulf Palinski, M.D., UCSD professor of medicine, Department of Medicine. "This raises the possibility that these different roles taken by PPAR-alpha and PPAR-gamma might be exploited therapeutically through the use of combined drugs to synergistically inhibit the development of atherosclerosis."

The study’s observations also have potentially important clinical implications for the millions of patients who have Type 2 diabetes mellitus, Glass said, adding that "diabetes is a strong risk factor for the development of atherosclerosis and its clinical complications. The findings presented in this study raise the possibility that the use of anti-diabetic drugs that activate PPAR-gamma, such as Rosiglitazone and Piaglitazone, will not only reduce the risk of developing atherosclerosis by improving blood glucose levels, but also by acting directly within the artery wall. Clinical studies now in progress should determine whether the use of these drugs reduce cardiovascular events in diabetic patients over the next few years."

The study’s first author was Andrew C. Li, M.D., UCSD Department of Cellular and Molecular Medicine. Additional authors were Christoph J. Binder, M.D., Ph.D., Jennifer W. Pattisson, B.S., and Joseph L. Witztum, M.D., UCSD Department of Medicine; Alejandra Guitierrez, B.S. and Roger A. Davis, Ph.D., Department of Biology, San Diego State University; Kathleen K. Brown, Ph.D. and Timothy M. Willson, Ph.D., Glaxo-Smith-Kline, North Carolina; Christine R. Plotkin, B.S., Genomics Core, Center for AIDS Research, Veterans Medical Research Foundation, La Jolla, CA; and Annabel Valledor, Ph.D., UCSD Department of Cellular and Molecular Medicine.

Sue Pondrom | EurekAlert!
Further information:
http://www.ucsd.edu

More articles from Health and Medicine:

nachricht 3D images of cancer cells in the body: Medical physicists from Halle present new method
16.05.2018 | Martin-Luther-Universität Halle-Wittenberg

nachricht Better equipped in the fight against lung cancer
16.05.2018 | Friedrich-Alexander-Universität Erlangen-Nürnberg

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: LZH showcases laser material processing of tomorrow at the LASYS 2018

At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.

At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...

Im Focus: Self-illuminating pixels for a new display generation

There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?

At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...

Im Focus: Explanation for puzzling quantum oscillations has been found

So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics

Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...

Im Focus: Dozens of binaries from Milky Way's globular clusters could be detectable by LISA

Next-generation gravitational wave detector in space will complement LIGO on Earth

The historic first detection of gravitational waves from colliding black holes far outside our galaxy opened a new window to understanding the universe. A...

Im Focus: Entangled atoms shine in unison

A team led by Austrian experimental physicist Rainer Blatt has succeeded in characterizing the quantum entanglement of two spatially separated atoms by observing their light emission. This fundamental demonstration could lead to the development of highly sensitive optical gradiometers for the precise measurement of the gravitational field or the earth's magnetic field.

The age of quantum technology has long been heralded. Decades of research into the quantum world have led to the development of methods that make it possible...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Save the date: Forum European Neuroscience – 07-11 July 2018 in Berlin, Germany

02.05.2018 | Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

Unique scope of UV LED technologies and applications presented in Berlin: ICULTA-2018

12.04.2018 | Event News

 
Latest News

Designer cells: artificial enzyme can activate a gene switch

22.05.2018 | Life Sciences

PR of MCC: Carbon removal from atmosphere unavoidable for 1.5 degree target

22.05.2018 | Earth Sciences

Achema 2018: New camera system monitors distillation and helps save energy

22.05.2018 | Trade Fair News

VideoLinks
Science & Research
Overview of more VideoLinks >>>