Nitric Oxide

Exercise protects the heart via Nitric Oxide , researchers discover.

 

Exercise both reduces the risk of a heart attack and protects the heart from injury if a heart attack does occur. For years, doctors have been trying to dissect how this second benefit of exercise works, with the aim of finding ways to protect the heart after a heart attack.

       Nitric Oxide

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Researchers at Emory University School of Medicine have identified the ability of the heart to produce and store nitric oxide as an important way exercise protects the heart from injury.
Nitric oxide, a short-lived gas generated within the body, turns on chemical pathways that relax blood vessels to increase blood flow and activate survival pathways. Both the chemical nitrite and nitrosothiols, where nitric oxide is attached to proteins via sulfur, appear to act as convertible reservoirs for nitric oxide in situations where the body needs it, such as a lack of blood flow or oxygen.Nitric Oxide
The Emory team's results, published online in the journal Circulation Research, strengthen the case for nitrite and nitrosothiols as possible protectants from the damage of a heart attack.
The first author is John Calvert, PhD, assistant professor of surgery at Emory University School of Medicine. The senior author is David Lefer, PhD, professor of surgery at Emory University School of Medicine and director of the Cardiothoracic Research Laboratory at Emory University Hospital Midtown. Collaborators included scientists at University of Colorado, Boulder, and Johns Hopkins University.
"Our study provides new evidence that nitric oxide generated during physical exercise is actually stored in the bloodstream and heart in the form of nitrite and nitrosothiols. These more stable nitric oxide intermediates appear to be critical for the cardioprotection against a subsequent heart attack," Lefer says.
Timing is key -- the benefits of exercise don't last In experiments with mice, the researchers showed that four weeks of being able to run on a wheel protected them from having a coronary artery was blocked; the amount of heart muscle damaged by the blockage was less after the exercise period. Importantly, the mice are still protected a week after the wheel is taken away.
The researchers found that voluntary exercise boosted levels of an enzyme that produces nitric oxide (eNOS, endothelial nitric oxide synthase). Moreover, the levels of eNOS in heart tissue, and nitrite and nitrosothiols in the blood as well as heart tissue, stayed high for a week after exercise ceased, unlike other heart enzymes stimulated by exercise. The protective effects of exercise did not extend beyond four weeks after the exercise period was over, when nitrite and nitrosothiols in the heart returned to baseline.Nitric Oxide
In mice that lack the eNOS enzyme, exercise did not protect the heart from a coronary blockage, although these mice appeared to lack the ability to exercise as much as normal mice.
Another molecule that appears to be important for the benefits of exercise is the beta-3-adrenergic receptor, which allows cells to respond to the hormones epinephrine and norepinephrine. All of the beneficial effects of voluntary exercise are lost in mice that are deficient in this receptor. One of the effects of stimulating the receptor appears to be activating eNOS. Additional animal studies are currently underway in Lefer's lab to determine the potential benefit of beta-3-adrenergic receptor activating drugs following a heart attack.
The research was supported by the American Diabetes Association, the National Institutes of Health and the Carlyle Fraser Heart Center of Emory University Hospital Midtown.Nitric Oxide

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Story Source:
Materials provided by Emory University. Note: Content may be edited for style and length.

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Journal Reference:

1. J. W. Calvert, M. Elston, J. Pablo Aragon, C. K. Nicholson, B. F. Moody, R. L. Hood, A. Sindler, S. Gundewar, D. R. Seals, L. A. Barouch, D. J. Lefer. Exercise Protects Against Myocardial Ischemia-Reperfusion Injury via Stimulation of β₃-Adrenergic Receptors and Increased Nitric Oxide Signaling: Role of Nitrite and Nitrosothiols. Circulation Research, 2011; DOI: 10.1161/CIRCRESAHA.111.241117

Nitric oxide,

Nitric oxide,: A little molecule's remarkable feat -- prolonging life, worm study shows

 

Nitric oxide, the versatile gas that helps increase blood flow, transmit nerve signals, and regulate immune function, appears to perform one more biological feat -- prolonging the life of an organism and fortifying it against environmental stress, according to a new study.Nitric oxide,

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The study reveals that a roundworm called Caenorhabditis elegans, an animal widely used in laboratory studies of aging, lives significantly longer when fed bacteria capable of manufacturing Nitric oxide, . The tantalizing observation points to one of the mechanisms by which the microbiome, the trillions of microbial cells inhabiting our bodies, may play a vital role in our health.
Our own nitric oxide levels decrease as we get older, a decline that may contribute to normal aging, says Evgeny Nudler, PhD, the Julie Wilson Anderson Professor of Biochemistry at NYU Langone Medical Center, who led the new study. Supplemental bacteria, he speculates, might provide a healthy boost by supplying humans with some of the missing compound.
"In worms, we now know that bacteria can use nitric oxide not only to their own advantage but also to provide their host with a beneficial response, and the same thing could be true in a human gut," says Dr. Nudler. "It may well be the case that our commensal bacteria control some of our genes, at least in the gut, to protect those cells against stress and age-related decline." Commensal bacteria provide a benefit to the organisms they colonize.
Although humans and many other organisms have the enzyme needed to produce Nitric oxide, C. elegans does not. Instead, Dr. Nudler and his team report in the February 14th online issue of Cell that the worm can "hijack" the compound from the soil-dwelling Bacillus subtilis bacterium that is not only a favored food but also a common colonist within its gut. This resourcefulness, Dr. Nudler says, partially explains why worms fed B. subtilis live roughly 50 percent longer than counterparts fed Escherichia coli, which does not produce the compound.
In the new study, the average C. elegans lifespan increased by nearly 15 percent, to about two weeks, when researchers fed the worms nitric oxide-producing B. subtilis bacteria, compared to worms fed mutant B. subtilis with a deleted nitric oxide production gene. The research group also used fluorescent sensors to show that C. elegans does not make its own nitric oxide gas. When the worms were fed normal B. subtilis bacteria, however, the fluorescent signal appeared in their guts.
Fluorescent labeling and other tests also demonstrated that B. subtilis-derived nitric oxide penetrated the worms' tissues, where it activated a set of 65 genes. Some had been previously implicated in stress resistance, immune response, and increased lifespan, though others have unknown functions. Importantly, the researchers showed that two well-known regulatory proteins were essential for activating all of the genes.
"What we found is that Nitric oxide, gas produced in bacteria inside the worms diffuses into the worm tissue and activates a very specific set of genes acting through two master regulators, hsf-1 and daf-16, resulting in a high resistance to stress and a longer life," Dr. Nudler says. "It's striking that a small molecule produced by one organism can dramatically affect the physiology and even lifespan of another organism through direct cell signaling."
As part of nitric oxide's expansive repertoire, Dr. Nudler's lab previously showed how dangerous pathogens can exploit the molecule to fight off antibiotics. Despite its versatility, the new research suggests that nitric oxide is only one of multiple beneficial molecules produced by B. subtilis, Dr. Nudler says. His lab plans to look more closely at other potential mechanisms by which commensal bacteria can promote health and longevity, using the powerful and easily manipulated C. elegans system as a model.
The study co-authors include Ivan Gusarov, Laurent Gautier, Olga Smolentseva, and Ilya Shamovsky from the Department of Biochemistry and Molecular Pharmacology at NYU Langone Medical Center; and Svetlana Eremina and Alexander Mironov from the State Research Institute of Genetics and Selection of Industrial Microorganisms in Moscow, Russia.
The research was supported by the National Institutes of Health, the Biogerontology Research Foundation, and the Dynasty Foundation.Nitric oxide,

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Story Source:
Materials provided by NYU Langone Medical Center. Note: Content may be edited for style and length.

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Journal Reference:

1. Ivan Gusarov, Laurent Gautier, Olga Smolentseva, Ilya Shamovsky, Svetlana Eremina, Alexander Mironov, Evgeny Nudler. Bacterial Nitric Oxide Extends the Lifespan of C. elegans. 14 February 2013, Cell DOI: 10.1016/j.cell.2012.12.043