Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Research reveals how blood flow force protects blood vessels

29.01.2010
It is second nature for most of us that exercise protects against heart attack and stroke, but researchers have spent 30 years unraveling the biochemistry behind the idea. One answer first offered by researchers at the University of Rochester Medical Center is that athletic hearts push blood through arteries with greater force, which alone triggers reactions that protect against dangerous clogs in blood vessels.

In the latest study out of Rochester, published recently in the journal Blood, researchers demonstrated that they are very close to understanding every step in one flow-sensitive chain reaction that protects arteries. Each step provides an opportunity to mimic with drugs the proven ability of fast, steady blood flow to open up blood vessels and avert the inflammation and blood clots that come with atherosclerosis.

Past research at the Medical Center and elsewhere had determined that two genes, Krüppel-like factor 2 (KLF2) and endothelial nitric oxide synthase (eNOS), are turned on by blood flow force to reverse atherosclerosis, but not how. The current study found for the first time that flow causes a structural change in the enzyme histone deacetylase 5 (HDAC5), which in turn influences whether the two key genes are turned on.

"Obviously we should all be exercising to get our hearts pumping fast, which increases blood flow force through our vessels with all of these molecular benefits," said Zheng-Gen Jin, Ph.D., associate professor of Medicine within the Aab Cardiovascular Research Institute (CVRI) at the University of Rochester Medical Center, and corresponding author for the study. "Beyond that, the designers of future therapies may manipulate HDAC5 to fine-tune the action of protective genes."

Forcing It

The current study revolves around a signaling process called phosphorylation, in which enzymes called kinases attach a set of molecules called a phosphate group to a target to switch life processes on or off. In cells lining blood vessels (endothelial cells), the attachment of a phosphate group to an HDAC5 kicks it out of the cell's nucleus, perhaps by hiding a label that says it belongs there.

To study whether blood flow force represents one the signals that cause HDAC5 nuclear export, the team designed a virus to invade the cells and swap out the key building blocks that make possible its phosphorylation via blood flow force. Weiye Wang, also a member of the CVRI and first author of the paper, designed the virus. He also attached a fluorescent tag to HDAC5 in the mutated cells so the team could track it as it moved.

What the team found for the first time is that blood flow force (also called sheer stress) does indeed cause the phoshorylation, and export from the nucleus, of HDAC5 in endothelial cells. Importantly, the team also found that flow, by removing HDAC5 from the scene, forces it to break away from the molecule it usually attaches to in the nucleus: myocyte enhancer factor-2 (MEF2).

When free, MEF2 is known to drive the expression of Krüppel-like factor 2, which calls for increases in the supply of endothelial nitric oxide synthase (eNOS). eNOS then builds more of the nitric oxide that tells muscles surrounding arteries to relax, which increases blood flow and lowers blood pressure. When cells were engineered with HDAC5 incapable of being phosphorylated by flow, HDAC5 never left the nucleus, remained stuck to MEF2 and completely blocked the expression of KLF2 and eNOS.

Furthermore, taking away the ability of fast, steady flow to phosphorylate HDAC5 greatly weakened a second lifesaving benefit of flow: it prevents white blood cells from sticking to the cells lining blood vessels, an early, necessary step in the development of atherosclerosis. Fatty diets cause cholesterol deposits to build up within arterial walls, deposits that white blood cells "see" as infections and home in on to drive inflammatory disease. By increasing KLF2 expression, blood flow force is believed to prevent adhesion molecules on cells lining arteries from snagging white blood cells as they float by.

The team also showed through a series of experiments that flow-induced HDAC5 phosphorylation depends on the well known calcium/calmodulin pathway. The team theorizes that the force of flow changes the shape of calcium channels on the surface of endothelial cells, which enables calcium to rush into the cells and turn on calmodulin, which attaches to an as yet unidentified kinase that phosphorylates HDAC5.

Identifying such an enzyme would complete the first diagram of a flow-sensitive, protective signaling pathway. Jin's lab has zeroed in on calmodulin-dependent kinases as likely suspects, and is designing experiments that will shut down the genes coding for them to see if that stops the phosphorylation of HDAC5 by flow. Should that be the case, the team will seek to screen for drug candidates that encourage the action of these enzymes.

Along with Jin and Wang, the effort was led at the Aab CVRI by Chang Hoon Ha, Bong Sook Jhun and Chelsea Wong. Mukesh Jain led a partnering effort at the Case Western Reserve University School of Medicine. Much of the early work in area was done in the labs of Bradford Berk, M.D., Ph.D., CEO of the University of Rochester Medical Center, and Jun-ichi Abe, M.D., Ph.D., associate professor within the Aab CVRI. Funding for the work of Jin's team came from the American Heart Association, the American Diabetes Association and the National Heart, Lung and Blood Institute (NHLBI), part of the National Institutes of Health. The article was published online on Dec. 30, 2009.

"If we could free MEF2 from HDAC5 with a drug, we could mimic flow force to enhance KLF2 and eNOS expression and reverse inflammation in vessel walls," Jin said. "That promises to be extremely useful, and potentially to stave off disease underway in the blood vessels of humans."

Greg Williams | EurekAlert!
Further information:
http://www.urmc.rochester.edu

More articles from Health and Medicine:

nachricht Study tracks inner workings of the brain with new biosensor
16.08.2018 | Rheinische Friedrich-Wilhelms-Universität Bonn

nachricht Foods of the future
15.08.2018 | Georg-August-Universität Göttingen

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: It’s All in the Mix: Jülich Researchers are Developing Fast-Charging Solid-State Batteries

There are currently great hopes for solid-state batteries. They contain no liquid parts that could leak or catch fire. For this reason, they do not require cooling and are considered to be much safer, more reliable, and longer lasting than traditional lithium-ion batteries. Jülich scientists have now introduced a new concept that allows currents up to ten times greater during charging and discharging than previously described in the literature. The improvement was achieved by a “clever” choice of materials with a focus on consistently good compatibility. All components were made from phosphate compounds, which are well matched both chemically and mechanically.

The low current is considered one of the biggest hurdles in the development of solid-state batteries. It is the reason why the batteries take a relatively long...

Im Focus: Color effects from transparent 3D-printed nanostructures

New design tool automatically creates nanostructure 3D-print templates for user-given colors
Scientists present work at prestigious SIGGRAPH conference

Most of the objects we see are colored by pigments, but using pigments has disadvantages: such colors can fade, industrial pigments are often toxic, and...

Im Focus: Unraveling the nature of 'whistlers' from space in the lab

A new study sheds light on how ultralow frequency radio waves and plasmas interact

Scientists at the University of California, Los Angeles present new research on a curious cosmic phenomenon known as "whistlers" -- very low frequency packets...

Im Focus: New interactive machine learning tool makes car designs more aerodynamic

Scientists develop first tool to use machine learning methods to compute flow around interactively designable 3D objects. Tool will be presented at this year’s prestigious SIGGRAPH conference.

When engineers or designers want to test the aerodynamic properties of the newly designed shape of a car, airplane, or other object, they would normally model...

Im Focus: Robots as 'pump attendants': TU Graz develops robot-controlled rapid charging system for e-vehicles

Researchers from TU Graz and their industry partners have unveiled a world first: the prototype of a robot-controlled, high-speed combined charging system (CCS) for electric vehicles that enables series charging of cars in various parking positions.

Global demand for electric vehicles is forecast to rise sharply: by 2025, the number of new vehicle registrations is expected to reach 25 million per year....

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

LaserForum 2018 deals with 3D production of components

17.08.2018 | Event News

Within reach of the Universe

08.08.2018 | Event News

A journey through the history of microscopy – new exhibition opens at the MDC

27.07.2018 | Event News

 
Latest News

Air pollution leads to cardiovascular diseases

21.08.2018 | Ecology, The Environment and Conservation

Researchers target protein that protects bacteria's DNA 'recipes'

21.08.2018 | Life Sciences

A paper battery powered by bacteria

21.08.2018 | Power and Electrical Engineering

VideoLinks
Science & Research
Overview of more VideoLinks >>>