Biological trigger found that makes heart beat stronger in response to higher blood pressure.
The heart’s ability to adjust its contraction strength in response to increases in blood pressure can, when the condition becomes excessive, lead to arrhythmias and other serious heart conditions.
Now, a multidisciplinary research team at UC Davis has found a key biological trigger — a protein known as nitric oxide synthase, or NOS — that makes the heart beat stronger in response to higher blood pressure, along with a way to turn that trigger off when it becomes overactive.
“The heart is a robust pump that can compensate for short-term increases in blood pressure due to changes in physical and emotional conditions — like exercise or joy,” said study senior author Ye Chen-Izu, assistant professor of pharmacology and biomedical engineering at UC Davis. “But there is a darker side to that compensating system that could lead to life-threatening heart diseases. Our work opens up new avenues for preventing that outcome.”
Chen-Izu pulled together an interdisciplinary team of biophysicists, chemists, engineers, physiologists and cardiologists for a study of the biological system that controls contractility of the heart under mechanical stress such as that caused by high blood pressure. They put heart muscle cells from mice into a “cell-in-gel” system that simulates mechanical stress on cells. The system, which was developed by Chen-Izu and Kit Lam, chair of the UC Davis Department of Biochemistry and Molecular Medicine, is transparent, allowing changes at the molecular level to be observed as they occur in living cells through high-power microscopes.
A series of experiments showed that as mechanical stress increases, the release of calcium increases and strengthens heart contractions so it can pump harder against higher blood pressure. They identified NOS as the molecule that initially senses mechanical stress and creates nitric oxide, which activates ryanodine receptors that increase the calcium release.
The researchers also discovered that an isoform of NOS — neuronal nitric oxide synthase, or nNOS — was responsible for spontaneous calcium sparks that occurred when cells were supposed to rest, likely due to the buildup of nitric oxide from ongoing mechanical stress.
“Under conditions of heavy, persistent mechanical load, the heart’s fine-tuned calcium control system becomes unstable, causing irregular heartbeats,” said Chen-Izu, whose research focuses on the biomechanics and bioelectricity of heart disease. “This could explain why high blood pressure can increase arrhythmias, which may lead to sudden cardiac death, heart failure and stroke.”