Low oxygen levels in the heart have long been known to produce
life-threatening arrhythmias, even sudden death. Until now, it was not clear
how.
New findings, in
a study led by Steve A. N. Goldstein, MD, PhD, vice chancellor for Health
Affairs at the University of California, Irvine, and distinguished professor in
the UCI School of Medicine Departments of Pediatrics and Physiology &
Biophysics, reveal the underlying mechanism for this dangerous heart disorder.
“Our research
shows that within seconds, at low levels of oxygen (hypoxia), a protein called
small ubiquitin-like modifier (SUMO) is linked to the inside of the sodium
channels which are responsible for starting each heartbeat,” said Goldstein.
“And, while SUMOylated channels open as they should to start the heartbeat,
they re-open when they should be closed. The result is abnormal sodium currents
that predispose to dangerous cardiac rhythms.”
Titled, “Hypoxia produces pro-arrhythmic late sodium current in cardiac
myocytes by SUMOylation of NaV1.5 channels,” the study was published today in Cell
Reports. Lead author, Leigh D. Plant, PhD, assistant professor at
the Bouvé College of Health Sciences, Department of Pharmaceutical Sciences at
Northeastern University, was a former post-doctoral fellow with Dr. Goldstein.
Every heartbeat
begins when sodium channels open and ions to rush into heart cells — this
starts the action potential that causes the heart muscle to contract. When
functioning normally, the sodium channels close quickly after opening and stay
closed. Thereafter, potassium channels open, ions leave the heart cells, and
the action potential ends in a timely fashion, so the muscle can relax in preparation
for the next beat. If sodium channels re-open and produce late sodium currents,
as observed in this study with low oxygen levels, the action potential is
prolonged and new electrical activity can begin before the heart has recovered
risking dangerous, disorganized rhythms.
Fifteen years
ago, the Goldstein group reported SUMO regulation of ion channels at the
surface of cells, an unexpected finding since the SUMO pathway had been thought
to operate solely to control gene expression in the nucleus.
“This new
research shows how rapid SUMOylation of cell surface cardiac sodium channels
causes late sodium current in response to hypoxia, a challenge that confronts
many people with heart disease,” said Goldstein. “Previously, the danger of
late sodium current was recognized in patients with rare, inherited mutations
of sodium channels that cause cardiac Long QT syndrome, and to result from a
common polymorphism in the channel we identified in a subset of babies with
sudden infant death syndrome (SIDS).”
The information,
gained through the current study, offers new targets for therapeutics to
prevent late current and arrhythmia associated with heart attacks, chronic
heart failure and other life-threatening low oxygen cardiac conditions.
Source: https://som.uci.edu/news_releases/low-oxygen-predisposes-life-threatening-cardiac-arrhythmias.asp
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