Science CoverBiomedical engineering professor Dr. Ye Chen-Izu and her colleagues at UC Davis have taken a major step forward in advancing our understanding of how the heart adjusts to a changing mechanical load. Their paper is featured on the cover of the March 18, 2014 issue of Science Signaling.

Imagine trying to squeeze an equal amount of ketchup from a squirt bottle while you move your finger on and off the nozzle. Imagine doing this once a second for 80 years, 3 billion times. This is what your heart has to do. When you sit, when you stand, when you feel joy, when you’re scared, your blood pressure changes and your heart has to adjust how hard it contracts. It has been known for more than a century that the heart can adjust to the workload but how it adjusts remained unclear.

The Chen-Izu lab found that adjustment takes place at the level of the single heart muscle cell, called the cardiomyocyte. To discover this they had to device a way to mimic the changing mechanical load the cardiomyocyte experiences in the heart. To do this Dr. Chen-Izu’s team embed the cardiomyocytes in a 3-dimensional hydrogel developed by Dr. Kit S. Lam’s lab. With this ‘cell-in-gel’ system they can control the mechanical load on the cell during cardiomyocytes contraction.

They find that as the mechanical load increases, the amount of calcium release during each heartbeat also increases, which makes the cardiomyocyte contract more strongly. In the whole heart, the stronger contraction would compensate for the larger load allowing the heart to pump about the same amount of blood into circulation. The team went on to identify the key molecules that sense mechanical load and translate it to biochemical signals to regulate calcium release. They found that a key molecule is the nitric oxide synthase 1 (NOS1, also called nNOS) which is activated by mechanical stress and catalyzes the formation of nitric oxide; then nitric oxide activates the ryanodine receptor which in turn increases the calcium release. They also found that another isoform NOS3 (also called eNOS) has a smaller role in regulating calcium release.

To understand why nNOS and eNOS have different effects, Dr. Chen-Izu teamed up with Dr. Tim Zhang to use super-resolution imaging to measure the distances between molecules. They found that nNOS is located much closer to ryanodine receptors than eNOS. This means that the nitric oxide generated by nNOS can reach the ryanodine receptor in shorter time and at higher concentration than that by eNOS. Thus, localized nitric oxide signaling may underlie the different roles of nNOS and eNOS in regulating calcium release. Such fine-tuned signaling processes help the heart to adjust to different mechanical loads.

However, there is a darker side to the load compensating system. They found that under heavy mechanical load the calcium control system can become unstable. When this happens, cardiac arrhythmias could arise. The increased incidence of arrhythmias in people with high blood pressure might be caused by the instability of the calcium control system. Chen-Izu’s team also found that the calcium control system might be restabilized by inhibiting nNOS. This discovery opens up new pharmacological avenues for preventing life-threatening arrhythmias, which often accompany high blood pressure and other forms of mechanical stress induced heart diseases.

Mechanochemotransduction During Cardiomyocyte Contraction Is Mediated by Localized Nitric Oxide Signaling.

Zhong Jian, Huilan Han, Tieqiao Zhang, Jose Puglisi, Leighton T. Izu, John A. Shaw, Ekama Onofiok, Jeffery R. Erickson, Yi-Je Chen, Balazs Horvath, Rafael Shimkunas, Wenwu Xiao, Yuanpei Li, Tingrui Pan, James Chan, Tamas Banyasz, Jil C. Tardiff, Nipavan Chiamvimonvat, Donald M. Bers, Kit S. Lam, Ye Chen-Izu.

Science Signaling [Published on March 18, 2014]