Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New ’molecular switch’ protein protects the heart from major cardiovascular damage

23.01.2006


U-M researchers report dramatic benefits from a single amino acid substitution in troponin I cardiac muscle protein



It’s just one little amino acid, but it makes all the difference in protecting the heart from the harmful effects of heart attack and cardiac failure. Researchers from the University of Michigan Medical School suggest this amino acid, called histidine, could be the key to a new therapy for cardiovascular disease.

In a study to be published Jan. 22 in Nature Medicine as an advance online publication, U-M scientists describe how they created a modified form of a heart muscle protein called troponin I and how it improved cardiac function in mice and in damaged human heart cells. The secret was using genetic engineering technology to replace one amino acid called alanine, found in the adult form of troponin I, with a histidine from the fetal form of the same protein.


"The most important finding of our study was that this modified troponin I protein dramatically improved heart function under a variety of conditions associated with cardiovascular damage and heart failure," says Sharlene Day, M.D., an assistant professor of internal medicine in U-M’s Cardiovascular Center and co-first author of the Nature Medicine paper.

"This study provides the first evidence that a single histidine substitution in troponin I can improve short and long-term cardiac function in laboratory mice with heart failure," says Joseph M. Metzger, Ph.D. – a professor of molecular and integrative physiology and of internal medicine in the U-M Medical School. "The fact that we also were able to rescue the functionality of damaged human heart cells is a significant advance."

Metzger believes U-M’s modified troponin I protein could become the basis of a new gene therapy or cell-based therapy for heart disease and heart failure. Progressive heart failure affects 4.8 million Americans. Despite current medical and surgical therapies, mortality remains high.

Troponin I is an important cardiac muscle regulatory protein that controls the calcium sensitivity of heart muscle cells. The ability to respond to calcium is important, because it’s what causes the heart to contract efficiently and pump blood through the body. When blood flow to the heart is compromised, such as during a heart attack, acid accumulates in cardiac cells – a condition called acidosis. This causes cells to become less responsive to calcium, which can lead ultimately to heart damage and cardiac failure.

During embryonic development, the fetal form of troponin I is present in the fetal heart, which makes it more resistant than the adult heart to the harmful effects of acidosis and low oxygen that can occur during pregnancy or delivery. This means that fetal hearts largely retain their ability to respond to calcium under adverse conditions.

"Shortly before or after birth, the gene for fetal troponin I is turned off and the adult gene is turned on," says Margaret Westfall, Ph.D., an assistant professor of surgery in U-M’s Cardiovascular Center and co-first author of the Nature Medicine paper. "Although the adult form of troponin I is more susceptible to the harmful effects of acidosis, it has other important properties that enable the adult heart to respond to hormones during exercise and periods of stress."

In essence, U-M researchers created a "genetic hybrid" of troponin I to combine the advantages of the fetal and adult form of the protein. According to U-M scientists, the modified protein helps the heart respond to a harsh intracellular environment by boosting its performance during periods of stress.

"By making this single histidine substitution in the adult form of troponin I, we retain hormonal responsiveness and provide protection from acidosis in the same molecule," Day says. "Several heart conditions can cause acidosis in the adult heart, most notably when the heart is deprived of oxygen and nutrients due to compromised blood flow – a condition known as ischemia. When ischemia is prolonged, it can cause permanent heart muscle damage in the form of a heart attack."

"The transition from the fetal to adult form of troponin I worked well throughout most of human evolution, but the problem now is our Western lifestyle and diet, which can damage the heart," Metzger explains. "Plus, people live into their 80s or 90s, so there’s more time for ischemic heart disease and heart failure to develop."

In a series of experiments, U-M researchers studied the effects of the histidine substitution in troponin I on 1) transgenic mice with the modified form of the protein and normal littermates without the modified protein, 2) hearts removed from both types of research mice, and 3) heart cells called myocytes, which were isolated from rats and from severely damaged human hearts of U-M Health System patients who received heart transplants.

In experiments with isolated myocytes, Westfall used a virus to deliver the modified troponin I gene. When she analyzed cells for expression of troponin I with the histidine substitution, Westfall discovered that "you don’t need 100 percent gene replacement to see a biological effect in individual myofilaments. We see favorable effects at 20 percent to 50 percent replacement," she says.

To create the damaging conditions that develop in heart muscle cells when clogged blood vessels or a heart attack interrupt the heart’s oxygen supply, Day tied off one of the main arteries carrying blood to the hearts of mice in the study. Day found that hearts from transgenic mice performed far better after the procedure than hearts from mice without modified troponin I.

The U-M research team also found that hearts from transgenic mice contracted more efficiently and used less energy to perform more work than hearts from non-transgenic littermates.

The U-M research team is studying the effects of the genetically engineered troponin I protein in other research animals and exploring mechanisms responsible for its heart-protective effect. They believe the modified troponin I protein senses changes within cardiac muscle cells and responds by improving the cells’ ability to contract efficiently in response to stress.

The University of Michigan has filed a patent application on the genetically engineered troponin I protein and its method for regulating cardiac performance. U-M is looking for a commercialization partner to market the technology.

Sally Pobojewski | EurekAlert!
Further information:
http://www.umich.edu

More articles from Life Sciences:

nachricht A novel socio-ecological approach helps identifying suitable wolf habitats
17.02.2017 | Universität Zürich

nachricht New, ultra-flexible probes form reliable, scar-free integration with the brain
16.02.2017 | University of Texas at Austin

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Biocompatible 3-D tracking system has potential to improve robot-assisted surgery

17.02.2017 | Medical Engineering

Real-time MRI analysis powered by supercomputers

17.02.2017 | Medical Engineering

Antibiotic effective against drug-resistant bacteria in pediatric skin infections

17.02.2017 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>