Mice with glowing green hearts have yielded the latest clue in the search for molecules involved in structural heart disease. Vanderbilt University Medical Center investigators found that blocking the activity of a single protein, called CaM kinase, in the mouse heart protects against the damaging effects of a heart attack.
The findings, published in the April issue of Nature Medicine, suggest that medicines designed to block CaM kinase activity may be useful for treating patients with structural heart disease and myocardial dysfunction.
Heart disease remains the number one killer in the United States. Most of that disease is in individuals who have suffered a heart attack or who have had changes in the heart muscle, including hypertrophy and dilation, for other reasons, said Mark E. Anderson, M.D., Ph.D. Betty and Jack Bailey Professor of Cardiovascular Medicine at Vanderbilt and the senior investigator of the current study.
"People with structural heart disease die suddenly from electrical instability – arrhythmias – and also because the heart fails to function properly as a pump," said Anderson, who is also associate professor of Medicine and Pharmacology.
Anderson and Roger J. Colbran, Ph.D., associate professor of Molecular Physiology & Biophysics at Vanderbilt University Medical Center, have collaborated for a number of years to study the role of the protein CaM kinase in signaling pathways that underlie the heart's electrical stability and maintenance of normal rhythm. Several years ago, they demonstrated in a mouse model of cardiac hypertrophy that blocking CaM kinase activity suppresses arrhythmias.
At the same time, evidence from other laboratories began to suggest that CaM kinase's role in structural heart disease went beyond the electrical signaling network. CaM kinase protein was consistently elevated in patients and animals with structural heart disease. And mouse lines genetically engineered to produce excess CaM kinase developed a convincing model of structural heart disease – the hearts thickened, then dilated, and the animals died suddenly, Anderson said.
"We were interested in closing the loop: if we targeted CaM kinase for inhibition, could we prevent or reduce structural heart disease phenotypes that were relevant in patients?" Anderson asked.
Because existing CaM kinase inhibitor drugs affect a number of different targets, the investigators opted to use a genetic approach to block CaM kinase activity. Rong Zhang, M.D., Ph.D., research assistant professor of Medicine at Vanderbilt, engineered mice to express a peptide inhibitor of the kinase protein, or a control peptide that did not block the kinase, only in heart cells, and only after birth. Zhang linked the peptide inhibitor and the control peptide to a green fluorescent protein to confirm expression in the heart, giving the engineered mouse hearts a green glow.
The researchers surgically created large heart attacks and studied how the hearts responded. In non-engineered mice and mice with control peptide, the hearts underwent structural remodeling – the surviving heart muscle thickened and hypertrophied in an attempt to compensate, then it dilated and failed. Mice expressing CaM kinase inhibitor fared better. "The mice with genetic CaM kinase inhibition didn't undergo such severe remodeling and their cardiac function remained substantially improved," Anderson said.