Heart Cells' Suicides
By Jason Socrates Bardi
The influences of Roberta Gottlieb's early days growing up
on a cattle ranch in rural New Mexico continue to be meaningful
in her life today as an associate professor in the Department
of Molecular and Experimental Medicine (MEM) at The Scripps
Research Institute.
One influence of those days on the open range is the sense
of self-reliance and creativity they instilled in her. She
recalls how her father once saw a metal and wood device for
immobilizing calves in order to brand them at a cattle show
and came home and built the same sort of thing from scratch.
And the endless expanse of the high desert was fertile ground
for thinking creatively.
"You ended up coming up with a lot of things on your own,"
she says, adding that this is something that she finds absolutely
necessary in the cutting-edge world of basic biology.
The other way that the rancher's life prepared her for work
in the MEM's Division of Hematology is that she used to get
up every morning before sunrise in order to tend to the herd.
Today, she has no herd, but rising early is still de rigeur
to attend to her laboratory.
Apoptosis in the Heart
At Scripps Research, Gottlieb and her colleagues study an
area of emerging importance in the biology of heart disease—the
process of apoptosis in heart cells.
Apoptosis, also called programmed cell death or cell suicide,
is a methodical process whereby cells take deliberate steps
to achieve their own demise. Apoptotic cells express proteins
that break down their DNA, DNA repair enzymes, and structural
proteins like lamins and actin. The morphology of a cell changes
as it undergoes apoptosis, shrinking away.
Despite how dramatic this may sound, apoptosis is a calm
sort of death in contrast to necrosis, another major form
of cell death in the heart that is characterized by sometimes
violent cell lysis and inflammation.
When Gottlieb came to Scripps Research in the early 1990s
to work in the laboratory of MEM Professor Bernard Babior,
she was interested in looking at apoptosis in the immune cells
known as neutrophils. She had finished her medical degree
several years before, and had completed her residency and
fellowship in pediatric oncology, and a postdoctoral fellowship
in molecular biology at the University of California, San
Diego.
At that time, scientists assumed that the death of heart
cells after ischemia was by necrosis. While a visiting scientist
in the Babior lab, cardiologist Robert Engler wondered whether
apoptosis might also be taking place. Gottlieb joined the
team and applied a newly-described method of detecting apoptotic
cells in situ, and they soon were the first team to demonstrate
that apoptosis occurred in the heart after ischemia/reperfusion.
Apoptosis, it turns out, is a big issue in heart attacks,
which are the number one killer in the United States. According
to the National Heart, Lung, and Blood Institute, about 12.6
million Americans suffer from coronary heart disease, the
most common form of heart disease. This disease often leads
to an acute myocardial infarction, the technical term for
a heart attack. Some 1.1 million Americans suffer heart attacks
each year, and approximately 515,000 of these are attacks
are fatal.
Currently, the main treatments for heart attacks address
the initial thrombus or blockage to the artery in order to
restore blood flow to the heart. Doctors use thrombolytic
"clot busting" drugs to dissolve the blockage chemically,
or angioplasty—tiny balloon catheters often followed
by a wire mesh stent—to mechanically prevent the artery
from collapsing.
Over the long term, myocardial infarction leads to fibrosis,
the formation of scar tissue that replaces dead heart tissue.
Heart attack survivors often have weakened hearts because
this scar tissue cannot function properly. These patients
often require additional procedures, such as the insertion
of pacemakers or heart transplants.
The blockage starves the heart tissue of oxygen, triggering
a whole cascade of events. However, tissue damage may continue
to worsen in the hours following the attack, even after the
clot is gone. In fact, the restoration of blood flow triggers
additional injury due in part to dramatic shifts in intracellular
ion concentrations, formation of damaging oxygen radicals,
and inflammation. Additional damage occurs because the ischemia
may have made the heart cells trigger their own deaths through
apoptosis.
"As you restore blood flow," says Gottlieb, "you create
a number of changes that are deleterious and can trigger cell
death."
Reperfusion is necessary for patients who have heart attacks,
for if you do not do it, the heart cells will die from necrosis
and the patients will not live. The irony of restoring blood
flow in a blocked artery after a heart attack is that the
reperfusion may cause some additional damage, although it
is still preferable to leaving the heart muscle without blood
flow permanently.
Acid Drain
In a heart that has been cut off of its oxygen supply from
an ischemic blockage, the heart cells do what they can to
survive.
Cells that do not have enough oxygen begin to perform glycolysis,
the breakdown of glucose, in order to supply energy in the
form of a molecule called ATP. But glycolysis generates lactic
acid as a by-product, and so ischemia leads to a drop in the
intracellular pH (the cells become more acidic).
Facing the accumulation of lactic acid, the cells try to
normalize their pH by pumping the acidic molecules out of
the cell. This works, but it also can trigger the exchange
of ions in and out of the cell.
Normally, cells maintain distinct "gradients" of ions like
sodium, potassium, and calcium, and these differences in concentration
of ions on the inside and outside of cells establish chemical
and electrical driving forces that can be used to perform
a range of basic cellular operations. But when ions like sodium
and calcium are exchanged following ischemia, they might be
exchanged contrary to their normal concentrations.
Sodium ions, for instance, are normally kept low inside
cells, but following reperfusion, the intracellular concentration
of sodium goes up. So does calcium.
In order to deal with the increase in calcium, heart cells
rely on their mitochondria. Mitochondria are the highly complex
organelles located inside virtually every cell in the human
body that normally supply cells with most of the energy they
need. But during ischemia, the mitochondria try to reduce
the levels of calcium inside the cell by sequestering it.
This influx of calcium into the mitochondria triggers a response
that results in the catastrophic release of proteins from
within the mitochondrial membrane.
"This makes it difficult for the cell to recover because
[without functioning mitochondria], the cell doesn't have
an energy synthesis machine," Says Gottlieb.
Worse, the ruptured mitochondria also release factors that
trigger apoptosis, through activation of proteins that break
down proteins (called caspases) and others called endonucleases,
which chew up DNA in the cell.
Another event that happens in the mitochondria following
reperfusion is the production of what are referred to as "reactive
oxygen species." These are compounds like hydrogen peroxide
and oxygen radicals that are highly reactive and can react
with lipids and proteins in the mitochondrial membrane to
produce oxidized lipid and protein molecules. These can also
compromise a cell's function.
"It becomes a very complicated set of events that are going
on simultaneously—like a three-ring circus," says Gottlieb.
"Any one of [these events] alone can result in the death of
the cell."
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