Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


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


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:

More articles from Life Sciences:

nachricht First time-lapse footage of cell activity during limb regeneration
25.10.2016 | eLife

nachricht Phenotype at the push of a button
25.10.2016 | Institut für Pflanzenbiochemie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Etching Microstructures with Lasers

Ultrafast lasers have introduced new possibilities in engraving ultrafine structures, and scientists are now also investigating how to use them to etch microstructures into thin glass. There are possible applications in analytics (lab on a chip) and especially in electronics and the consumer sector, where great interest has been shown.

This new method was born of a surprising phenomenon: irradiating glass in a particular way with an ultrafast laser has the effect of making the glass up to a...

Im Focus: Light-driven atomic rotations excite magnetic waves

Terahertz excitation of selected crystal vibrations leads to an effective magnetic field that drives coherent spin motion

Controlling functional properties by light is one of the grand goals in modern condensed matter physics and materials science. A new study now demonstrates how...

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

3-D-printed structures shrink when heated

26.10.2016 | Materials Sciences

Indian roadside refuse fires produce toxic rainbow

26.10.2016 | Health and Medicine

First results of NSTX-U research operations

26.10.2016 | Physics and Astronomy

More VideoLinks >>>