September 14, 2006
Mouse Gene Knock-Out Blocks Atherosclerosis

Genetically engineered lab mice once again produce a research result with very important implications for human health.

(Philadelphia, PA) - Building on previous work, researchers at the University of Pennsylvania School of Medicine have found that deleting an inflammation enzyme in a mouse model of heart disease slowed the development of atherosclerosis. What's more, the composition of the animals' blood vessels showed that the disease process had not only slowed, but also stabilized. This study points to the possibility of a new class of nonsteroidal anti-inflammatory drugs (NSAIDs) that steer clear of heart-disease risk and work to reduce it.

Drugs that block the same gene (or its protein product) that was knocked out in these mice might also stop the development of arterial plaque that clogs up our circulatory systems. Mouse knock-out experiments once again deliver the goods.

Senior author Garret FitzGerald, MD, Director of the Institute for Translational Medicine and Therapeutics at Penn, and colleagues report their findings this week in the online edition of the Proceedings of the National Academy of Sciences.

NSAIDs like ibuprofen (Advil) and naproxen (Naprosyn) relieve pain and inflammation by blocking the cyclooxygenases, or COX enzymes (COX-1 and COX-2). These enzymes help make fats called prostaglandins. COX-2 is the most important source of the two prostaglandins - PGE2 and prostacyclin - that mediate pain and inflammation. However, COX-2-derived PGE2 and prostacyclin may also protect the heart, and loss of this function - particularly suppression of prostacyclin - explains the risk of heart attacks from NSAIDs that inhibit COX-2, such as rofecoxib (Vioxx), valdecoxib (Bextra), and celecoxib (Celebrex).

The problems with COX-2 inhibitors have prompted the search for alternative drug targets that suppress pain and inflammation yet are safe for the cardiovascular system. One possibility is an enzyme called mPGES-1, which converts PGH2 (a chemical product of COX-2) into PGE2. Previous studies at other institutions in mice lacking mPGES-1 suggest that inhibitors of this enzyme might retain much of the effectiveness of NSAIDs in combating pain and inflammation. However, unlike COX-2 inhibition or deletion, the Penn researchers had found that mPGES-1 deletion did not elevate blood pressure or predispose the mice to thrombosis. This work began to raise the possibility that mPGES-1 inhibitors might even benefit the heart.

In the PNAS study, the researchers studied the impact of deleting the mPGES-1 gene in mice predisposed to hardening of the arteries. Removing the enzyme had a dramatic effect on the development of the disease. "Both male and female mice slowed their development of atherosclerosis," explains first author Miao Wang, PhD, a postdoctoral fellow in the Penn Institute.

The composition of the blood vessels of the transgenic mice suggested that the disease process had not only slowed, but also stabilized. Collaborators Ellen Pure and Alicia Zukas at the Wistar Institute examined the detailed structure of the diseased arteries. Deleting mPGES-1 resulted in a dramatic change in the cellular constituents of the atherosclerotic plaques seen in the transgenic mice. In the absence of the enzyme, the diseased vessels were depleted of immune cells called macrophages, which led to the predominance of vascular smooth muscle cells in blood vessel walls. In turn, this led to a switch in the form of collagen - a fibrous structure that contributes to the fabric of plaques - to a more stable and benign form.

"It seems that it is the complete reverse of the mechanism that creates problems for COX-2 inhibitors," says FitzGerald. Mice lacking mPGES-1 boost their production of prostacyclin, the major heart-protecting fat produced by COX-2. They do this by redirecting prostacylcin to vascular smooth muscle cells. The same mechanism explains the group's earlier findings on blood pressure and thrombosis.

"It remains to be determined whether specific inhibitors of mPGES-1 can replicate the consequences of removing the gene" explains FitzGerald, "And if so, whether these results will translate from mice to humans."

In the meantime, these results, say the investigators, will fuel interest in the possibility of a new class of "super NSAIDs," which may not just avoid the risk of heart disease, but also actually work to diminish it.

The build-up of artery plaque is going to become totally preventable and in short order. Diet alone already can reduce the risk enormously. Eat the ape diet if you want to lower your risk of heart disease, stroke and other diseases..

Cholesterol-lowering statin drugs already possess some of the anti-inflammatory qualities of the "super NSAIDs" mentioned in the previous article.

University of California, Davis researchers have shown that statins not only improve cholesterol levels, but also dramatically reduce disease-causing inflammation in patients with metabolic syndrome -- a condition defined by symptoms that include abdominal obesity and high blood pressure.

...

The UC Davis team conducted a double-blind, randomized, placebo-controlled study in which they gave a standard daily dose of a statin (Simvastatin or placebo) to 50 patients with metabolic syndrome. After eight weeks, they measured cholesterol levels, as well as biomarkers of inflammation in the circulation, but more importantly, in cells pivotal in all stages of plaque formation, the monocytes. They found, as expected, that statin lowered low-density-lipoprotein- cholesterol and non-high-density-lipoprotein-cholesterol levels, both of which the American Heart Association guidelines target for treatment of metabolic syndrome.

Jialal and his colleagues also found marked reductions in two pivotal biomarkers of inflammation: C-reactive protein (CRP) and interleukin-6. While these markers are typically elevated in insulin resistance, a condition that precedes the development of diabetes, statin therapy reduced these levels by 36 percent and 44 percent, respectively.

Chronic inflammation is harmful and widespread.

As for people who have a need to take one of the existing NSAIDs, a recent pair of papers in the Journal of the American Medical Association found that Celebrex does not pose as large of a heart risk as Vioxx.

In one paper, three researchers at Harvard examined 114 clinical trials of Vioxx and other drugs and found that Vioxx was linked to substantially higher rates of increased blood pressure than was Celebrex, a similar painkiller, which is still sold.

In the other paper, two Australian researchers found that Vioxx appeared more dangerous than Celebrex or several older painkillers in observational studies, which examine the safety and effectiveness of drugs in real-world settings after they are approved.

David Graham of the FDA, writing as a private citizen, argues in JAMA that naproxen appears safest out of all the NSAIDs and probably is neutral in terms of risk of heart attack (MI or myocardial infarction).

Share |      Randall Parker, 2006 September 14 12:43 AM  Aging Genetics


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