"As Seen in GEN—Flashback" Volume 3, Number 4, July/August 1983
Molecular Cardiology Begins to Explain Heart Function, and Malfunction, Genetically
By Roger S. Johnson, Ph.D.
Recently, scientists have begun applying genetic engineering tools to the study of the mammalian heart, heralding a new understanding of heart disease, according to Johns Hopkins University cardiologist.
Anthony F. Cutilleta, M.D., associate professor of pediatrics, Division of Pediatric Cardiology, Johns Hopkins University School of Medicine, has shown that, at least in some conditions, heart cells respond to physiological stress by making new contractile proteins.
For example, if workload on the heart is increased by high blood pressure in the ventricle, the cells synthesize messenger RNA (mRNA) for myosin, the major muscle protein. The new myosin is an altered form, an isozyme of normal myosin. The change occurs rapidly and specifically in response to changes in physiological conditions placed on the heart, Dr. Cutilletta says.
This marks a new type of investigation of cardiology, where researchers traditionally have investigated anatomy, physiology and pharmacology. It follows earlier biochemical studies where scientists recently learned that animals have several cardiac myosin genes and that when their protein products are produced, the cardiac function changes.
When researchers constrict the aorta coming out of a rat’s left ventricle, the rat’s heart grows about 50 percent larger within a week. Furthermore, the isozyme of myosin that accounts for that muscle growth has a reduced enzyme activity. It catalyzes the release of energy from ATP at a slower rate. Scientists believe this compensates for the heavier workload on the heart muscle. Because the heart has to contract more slowly but with greater force, the slower ATPase may work better, maintaining normal cardiac output.
Dr. Cutilletta’s studies have concentrated on the changes following removal of the constricting band from the aorta. As aortic pressure returns suddenly to normal, myosin mRNA synthesis halts and normal rapid mRNA degradation continues.
Within a week the heart rapidly regresses back to its normal size, and during this one week transition period, when no new myosin is produced, cardiac function falls.
The heart pumps poorly because low-ATPase myosin may be inappropriate in these physiological conditions of normal pressure, Dr. Cutilletta suggests. The heart can compensate for changes in workload by changing its myosin isozyme, but following sudden shifts such as the release of an aortic band, the compensatory shift is too slow.
“The changes in mRNA account for the changes in heart mass and myosin ATPase activity and may explain the changes in cardiac function during regression,” he tells GEN.