November 11, 2013
WASHINGTON: Scientists have discovered that inhibition of a heart protein can reduce damage from heart attack and protect the organ from further injury.
The stop and start of blood flow to the heart during and after a heart attack causes severe damage to heart cells, reducing their capacity to function and potentially causing their death.
November 11, 2013
WASHINGTON: Scientists have discovered that inhibition of a heart protein can reduce damage from heart attack and protect the organ from further injury.
The stop and start of blood flow to the heart during and after a heart attack causes severe damage to heart cells, reducing their capacity to function and potentially causing their death.
Now, researchers at Temple University School of Medicine suggest that it is possible to limit the extent of that damage using a drug.
Researchers created a real-world clinical scenario in mice by mimicking blockage of an artery to induce heart attack and then administering a TNNI3K inhibitor.
When cardiac function was subsequently improved in treated mice versus untreated controls, the team realized that a TNNI3K inhibitor could have important clinical benefits for human patients.
"TNNI3K is found only in the heart, which makes it interesting biologically and therapeutically. Although its function was not well understood, TNNI3K lent itself to being a potential therapeutic target for heart attack," said Ronald Vagnozzi, lead author on the new study in the journal Science Translational Medicine.
The researchers found that TNNI3K expression is elevated in patients who are suffering from heart failure, which can develop in the years following heart attack.
To explore the significance of that elevation, they engineered mice to overexpress TNNI3K. They also created a second set of engineered mice, in which the protein was deleted.
When overexpressed, Vagnozzi and colleagues found that TNNI3K promoted the injury of heart tissue from ischemia (blockage of blood flow) and reperfusion (restoration of blood flow) during and after a heart attack.
TNNI3K overexpression in heart cells encouraged the production of superoxide, a reactive molecule from mitochondria, and activated p38 mitogen-activated protein kinase (MAPK), an enzyme that responds to stress signals in cells.
The combined result of those activities was impaired mitochondrial function and heart cell death, which worsened ischemia/reperfusion injury.
The opposite occurred in mice in which TNNI3K had been deleted – superoxide production and p38 activation were reduced, and injury to the heart was limited. Reductions in heart dysfunction and fibrosis (hardening of heart tissue) were also observed.
The team then collaborated with the pharmaceutical company GlaxoSmithKline (GSK) to identify compounds that were capable of blocking TNNI3K activity.
Treatment of wild-type (nonengineered) mice with the compounds following heart attack produced effects that were similar to those observed in mice with TNNI3K deletion.
Courtesy: PTI
