Scientists have discovered a compound that could lead to new treatments for heart attacks as well as methods to protect hearts during open heart surgery and other situations in which blood flow to the heart is interrupted.In the process, the researchers uncovered cellular mechanisms that help explain how alcohol can protect against heart attack damage. In addition, they have uncovered a possible key to reducing chest pain and the heart attack damage among millions of people of East Asian descent who are genetically unable to respond to nitroglycerin and other cardiovascular treatments.

A research team of scientists at Stanford and Indiana universities schools of medicine reports in the Sept. 12 issue of the journal Science that by jump-starting a particular enzyme they were able to significantly reduce the amount of cell death caused by lack of blood flow to the heart.

The group, led by Daria Mochly-Rosen, Ph.D., professor of chemical and systems biology at Stanford, found that administering a compound called Alda-1 activated the enzyme, reducing heart muscle damage in experiments involving rats.

First, however, the researchers studied various mechanisms known to provide cardioprotection to heart muscle cells, including the use of ethanol, to better understand how those mechanisms worked. That work revealed a cellular signaling system that activated a particular enzyme called ALDH2.

“The idea was to find a small molecule that could bypass the signaling process and activate the enzyme directly,” said Thomas D. Hurley, Ph.D., professor of biochemistry and molecular biology and director of the Center for Structural Biology at the IU School of Medicine. Hurley’s research has included years of study of the ALDH2 enzyme.

Although the Alda-1 molecule reduced heart tissue damage in laboratory tests, years of work will be necessary to refine the compound into a version that would be potentially effective and safe for human use, Dr. Hurley said. That benefit could extend to about 40 percent of people of East Asian descent who carry a mutated form of the ALDH2 enzyme, which puts them at increased risk of cardiovascular damage.

Marauding molecules cause the tissue damage that underlies heart attacks, sunburn, Alzheimer’s and hangovers.  But scientists at the Stanford University School of Medicine say they may have found ways to combat the carnage after discovering an important cog in the body’s molecular detoxification machinery.

The culprit molecules are oxygen byproducts called free radicals.  These highly unstable molecules start chain reactions of cellular damage an escalating storm that ravages healthy tissue.

“We’ve found a totally new pathway for reducing the damage caused by free radicals, such as the damage that happens during a heart attack,” said Daria Mochly-Rosen, PhD, professor of chemical and systems biology and the senior author of a study reporting the new findings.  The research will appear in the Sept. 12 issue of Science.

Before the study, scientists knew that heart muscle could be preconditioned to resist heart attack damage for instance, moderate drinkers tend to have smaller, less severe heart attacks than teetotalers.  But scientists didn’t understand how pre-conditioning worked.

To figure out how alcohol protects heart muscle from free-radical damage, Mochly-Rosen’s team tested alcohol pretreatment in a rat heart-attack model.  They compared the enzymes activated during the attacks to those switched on with no alcohol.  Enzymes are the “doers” of the cellular machinery, catalyzing all of the biochemical reactions that form the basis of life.

Surprisingly, the treatment activated aldehyde dehydrogenase 2 (ALDH2), an obscure alcohol-processing enzyme.  Alcohol pretreatment increased the enzyme’s activity during heart attack by 20 percent, leading to a 27 percent drop in the associated damage.

“Although this enzyme was discovered a long time ago, my research group knew nothing about the enzyme except that it helps remove alcohol when people drink,” said Mochly-Rosen, who is also the senior associate dean for research in the School of Medicine and the George D. Smith Professor in Translational Medicine.

ALDH2 wasn’t one of the well-studied antioxidant players that the scientists expected to find fighting free-radical damage.  The enzyme neutralizes an aldehyde molecule, a toxic byproduct of the ethanol in alcoholic beverages.  But aldehydes are also formed in the body when free radicals react with fat molecules.

The body’s cells contain a lot of fat, Mochly-Rosen noted.  “It’s very easy for free radicals to find fat and oxidize it to aldehydes.”

Inside cells, the accumulating aldehydes permanently bind and damage cellular machinery and DNA.  Such damage occurs in many diseases, from heart attack and Parkinson’s to sun-induced aging of the skin.

After learning of ALDH2’s novel role in reducing the damage, the researchers searched for a molecule that could make the enzyme function even better.  They enlisted the Stanford High Throughput Bioscience Center, directed by David Solow-Cordero, PhD, to find a molecule that heightened the enzyme’s activity.

The winner of this contest was a tiny molecule that reduced heart attack damage by 60 percent in the rat model.  The molecule, Alda-1, has a surprising mode of action: it protects ALDH2 itself from aldehyde attack.  The enzyme, it turns out, was being hobbled by the very chemical it removes.

Because Alda-1 is small, it should be easy to adapt for pharmacological use, Mochly-Rosen said.  She expects the new molecule to have many possible drug applications.

“It has a huge potential use,” she said.  So far, Alda-1 has been tested only in the rat model, but Mochly-Rosen’s lab is investigating other possible applications, such as fighting neurodegenerative disease and sun damage on the skin.  The team also hopes to interest drug companies in human trials.

In addition to its lofty medical applications, Alda-1 could also have a much lowlier use: fighting hangovers.  Many nasty hangover symptoms are due to aldehyde buildup.

The tiny molecule may also improve alcohol tolerance and reduce susceptibility to free-radical diseases in people with a common ALDH2 mutation.  The mutation affects 40 percent of people of Asian descent and causes an intolerance for alcohol.

Atherosclerosis is a disease of the major arterial blood vessels that is often known as hardening of the arteries; it is one of the main causes of heart attack and stroke.  An important first step in the disease is a process known as intimal thickening, whereby the intimal layer of arterial blood vessels becomes thicker because cells known as smooth muscle cells (SMCs) migrate to the area and proliferate.  The protein sLRII is thought to play a key role in this process, although its specific mechanisms of action and significance are poorly understood.  In a new study, Hideaki Bujo of the Chibe University Graduate School of Medicine, Japan, Wolfgang Schneider of the Medical University of Vienna, Austria, and their colleagues reveal that sLRII is important for SMC migration.

Levels of sLRII in the bloodstream were shown to be associated with intimal thickening in patients with poorly-regulated abnormal levels of fat in the blood.  Furthermore, intimal thickening was markedly reduced in mice lacking sLRII.  SMCs from these mice failed to migrate in response to stimulation, indicating that the reduced intimal thickening probably results from reduced SMC migration.  The authors therefore suggest that sLRII may serve as a novel marker for intimal thickening and atherosclerosis

Being male increases your risk of diseases caused by the inappropriate formation of a blood clot (a process known as thrombosis), such as heart attack and stroke, but the reasons for this are not completely understood.  However, Ethan Weiss and colleagues at the University of California, San Francisco, have used a mouse model of thrombosis to shed new light on this matter.

Thrombosis-related proteins are made in the liver, where expression of the genes containing the information needed for their generation is regulated by growth hormone (GH), which is secreted in a sex-specific manner — males secrete GH in a pulsatile fashion, whereas females secrete GH continuously.  In this study, GH-deficient mice were protected from thrombosis in the model of disease.  When female GH-deficient mice were given pulsatile GH (to mimic the manner in which GH is secreted in males) their ability to form blood clots resembled male mice.  Conversely, when male GH-deficient mice were given continuous GH (to mimic the manner in which GH is secreted in females) their ability to form blood clots resembled female mice.  The authors therefore conclude that sex-specific patterns of GH release mediate the gender-associated differences observed in susceptibility to diseases caused by inappropriate thrombosis, information that they hope will be of help in the development of sex-specific treatments for thrombosis.