Researchers Discover Hydrogen Sulfide Is a Major Regulator of Blood Pressure

Anyone with a nose knows the rotten-egg odor of hydrogen sulfide, a gas generated by bacteria living in the human colon. Now an international team of scientists has discovered that cells inside the blood vessels of mice — as well as in people, no doubt — naturally make the gassy stuff, and that it controls blood pressure.

Having discovered that hydrogen sulfide, or H2S, is produced in the thin, endothelial lining of blood vessels, the researchers, including scientists from Johns Hopkins, report today in Science that H2S regulates blood pressure by relaxing blood vessels. As the newest member of a family of so-called gasotransmitters, this messenger molecule is akin in function, if not form, to chemical signals like nitric oxide, dopamine and acetylcholine that relay signals between nerve cells and excite or put the brakes on mind-brain activities.

“Now that we know hydrogen sulfide’s role in regulating blood pressure, it may be possible to design drug therapies that enhance its formation as an alternative to the current methods of treatment for hypertension,” says Johns Hopkins neuroscientist Solomon H. Snyder, M.D., a co-author of the paper.

Conducting their investigations using mice missing a gene for an enzyme known as CSE, long suspected as responsible for making H2S, the researchers first measured hydrogen sulfide levels in a variety of tissues in the CSE-deficient mice and compared them to normal mice. They found that the gas was largely depleted in the cardiovascular systems of the altered mice, engineered by Rui Wang, M.D., Ph.D., of Lakehead University in Ontario, and Lingyun Wu, M.D., Ph.D., of the University of Saskatchewan, Canada. By contrast, normal mice had higher levels — clear evidence that hydrogen sulfide is normally made by mammalian tissues using CSE.

Next, the scientists applied tiny cuffs to the tails of the mice and measured their blood pressure, noting spikes of about 20 percent, comparable to serious hypertension in humans.

Finally, the team tested how blood vessels of CSE-deficient mice responded to the chemical neurotransmitter methacholine, known to relax normal blood vessels. The blood vessels of the altered mice relaxed hardly at all, indicating that hydrogen sulfide was largely responsible for relaxation.

Because gasotransmitters are highly conserved in mammals, the findings of the research are believed to have broad applications to human physiology and disease.

“In terms of relaxing blood vessels, it looks like hydrogen sulfide might be as important as nitric oxide,” Snyder says, referring to the first gasotransmitter that two decades ago was discovered to regulate blood pressure.

Just because these two gas molecules perform similar functions, doesn’t mean they’re redundant, says Wang, the paper’s principal author. “Nature has added on layer upon layer of complexity to provide a better and tighter control of body function — in this case, of blood pressure.”

Studying gaseous messengers can be tricky, explains Snyder, an authority on nitric oxide (NO) whose lab in 1990 discovered that the enzyme triggering NO production is activated by a protein mechanism known as calcium-calmodulin.

“When a nerve fires, it releases a bit of neurotransmitter. Then it fires again, very quickly, and releases more of the neurotransmitter, which is always in reserve and at the ready in large storage pools called vesicles. However, gasses can’t be stored; they diffuse. So every time there’s a nerve impulse, an enzyme must be activated to make it,” he says.”

Although CSE, the enzyme that activates hydrogen sulfide, was characterized more than half a century ago, the new work is the first to reveal that it is activated in the same way as the nitric oxide-forming enzyme, thus establishing how hydrogen sulfide regulates blood pressure by relaxing blood vessels.

“It’s difficult to overestimate the biological importance of hydrogen sulfide or its implications in hypertension as well as diabetes and neurodegenerative diseases,” Wang says. “In fact, most human diseases probably have something to do with gasotransmitters.”

The research was supported by grants from the U.S. Public Health Service and the Canadian Institutes of Health Research as well as a Research Scientist Award.

Authors on the paper are Guangdong Yang, Lingyun Wu, Bo Jiang, Wei Yang, Jiansong Qi, Kun Cao, Qinghe Meng, all of the University of Saskatchewan, Canada; Wang of the University of Saskatchewan and Lakehead University, Canada; Shengming Zhang of Lakehead University, Canada; and Asif K. Mustafa, Weitong Mu and Snyder, all of Hopkins.

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Memories Selectively, Safely Erased in Mice

New and old memories have been selectively and safely removed from mice by scientists.

"While memories are great teachers and obviously crucial for survival and adaptation, selectively removing incapacitating memories, such as traumatic war memories or an unwanted fear, could help many people live better lives," says Dr. Joe Z. Tsien, brain scientist and co-director of the Brain & Behavior Discovery Institute at the Medical College of Georgia School of Medicine.

"Our work reveals a molecular mechanism of how that can be done quickly and without doing damage to brain cells," says the Georgia Research Alliance Eminent Scholar in Cognitive and Systems Neurobiology.

Dr. Tsien's research team, in collaboration with scientists at East China Normal University in Shanghai, were able to eliminate new and old memories alike by over-expressing a protein critical to brain cell communication just as the memory was recalled, according to research featured on the cover of the Oct. 23 issue of Neuron.

Dr. Tsien had already created a mouse that couldn't form memories by eliminating the NMDA receptor, which receives messages from other neurons. He then garnered international acclaim by making "Doogie," a smart mouse in which a subunit of the NMDA receptor is over-expressed. Younger brains have higher amounts of this NR2B subunit which leaves communication channels between brain cells open longer. That is why young people can learn faster than older adults.

This time he was examining downstream cascades of the NMDA receptor to learn more about memory formation. An abundant protein found only in the brain, called αCaMKII, was a logical place to look because it's a major signaling molecule for the NMDA receptor. He found that when he over-expressed αCaMKII while a memory was being recalled, that single memory was eliminated.

Receptors such as the NMDA receptor are like front doors to cells, providing an opening for signaling molecules such as calcium. Synapses are the point of communication between two cells, and NMDA receptors are on the receiving end of the message. Like people, neurons change with the signals they receive. "Learning changes the way cells connect to each other," says Dr. Tsien. To form a memory, the NMDA receptor is activated, which results in the insertion of AMPA receptors into those synapses and subsequent strengthening of the synaptic connections among hundreds of thousands of neurons. Scientists believe that αCaMKII plays an important role in the insertion of AMPA receptors into synapses during learning and subsequent strengthening of connections between neurons to create a memory.

Memory has four distinct stages: learning, consolidation, storage and recall. It has been difficult to dissect the molecular mechanisms of these stages because researchers lacked techniques to manipulate proteins quickly. For example, when researchers disable a gene suspected to play a role in the memory process, the deletion typically occurred throughout the entire period so it was impossible to tell which parts of processes were impaired. Previous technology would take several days to switch off a protein, which is the product of a gene.

So Dr. Tsien’s team developed a powerful chemical-genetic method that allows him to use a pharmacologic inhibitor to instantly turn αCaMKII off and on in a mouse that he genetically engineered to over express this signaling molecule. That enabled him to study exactly what happened if he threw off the natural balance during the retrieval stage.

Much as a war veteran remembers a fateful patrol when he was fired upon, mice can establish a very long-lasting emotional memory about a place if, for example, they receive a mild shock to the paws while there. The researchers showed if they over-expressed αCaMKII, this powerful memory was rapidly erased as the animals tried to retrieve them while other memories remained intact.

A similar approach was taken with object recognition memory, giving mice a couple of toys to play with then erasing their memory of one of them. "You will feel like every time, it's a new toy," says Dr. Tsien.

While the ability to rapidly erase a selective memory is exciting, he cautions that its translation to humans would be difficult at this stage. “We are barely at the foot of a huge mountain,” says Dr. Tsien. A possible strategy for humans would be a drug that mimics the αCaMKII over expression that researchers accomplished through genetic manipulation. Or, further downstream substrates that αCaMKII acts upon could become possible drug targets.

The research was funded by the National Institute of Mental Health, the National Institute on Aging and the Georgia Research Alliance.

By Toni Baker

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