The buildup of fat in the blood makes a bad situation worse - it
not only raises a person's risk for heart attack or stroke
but also
impairs the growth of new blood vessels. How excess fat in the blood - a
condition known as hyperlipidemia - blocks vessel growth was unclear,
but new work by researchers at Temple University School of Medicine
(TUSM) shows that a molecule known as caspase-1 plays a central role and
that preventing its activity could be the key to building new blood
vessels and restoring blood supply to oxygen-starved tissues.
"Caspase-1 acts as a lipid sensor in endothelial cells, which are
abundant in the inner lumen of blood vessels," explained Xiao-Feng Yang,
MD, PhD, FAHA, Professor of Pharmacology, Professor of Microbiology and
Immunology in the Center for Metabolic Disease Research, Professor in
the Cardiovascular Research Center and Professor in the Sol Sherry
Thrombosis Research Center at TUSM, and senior investigator on the new
study, which appears in print in the July 10 issue of the
Journal of Biological Chemistry.
"When lipids reach dangerously high levels in the circulation, the
caspase-1-inflammasome complex initiates inflammation in the blood
vessel," notes, Dr. Yang. "It turns out that caspase-1 signaling also
inhibits endothelial cell growth, undermining the ability of the
vasculature to recover from ischemic disease."
Ischemic diseases, which include heart attack, stroke, and peripheral
artery disease, are a leading cause of illness and death in the United
States. Ischemia starves tissues of blood and oxygen, resulting in
severe damage to the blood vessels in affected tissues. Finding ways to
therapeutically restore blood flow after ischemia without causing
further tissue injury is a major goal in metabolic cardiovascular
research.
Caspase-1 inhibition could prove to be hugely important in the
treatment of ischemic disease. In their new report, Dr. Yang and
colleagues show that the caspase-1 distress signals triggered by
hyperlipidemia produce different effects in endothelial cells of
differing size. In small endothelial cells, it triggers cell death, but
in larger cells, it is involved in endothelial cell activation, in which
the inner lining of the blood vessel undergoes a series of changes that
ultimately contribute to the high lipid-induced inflammatory response.
"The
growth status of endothelial cells is important to the inflammatory
process," according to Dr. Yang. The major growth signaling pathway in
endothelial cells is mediated by vascular endothelial growth factor
receptor-2 (VEGFR-2), which also happens to be necessary for
angiogenesis - the formation of new blood vessels.
In a series of experiments in human endothelial cells, Dr. Yang's
team-- in collaboration with Hong Wang, MD, PhD, FAHA, EMBA, Associate
Dean of Research, Director of the Center for Metabolic Disease Research,
Professor of Pharmacology, Professor in the Cardiovascular Research
Center and Professor in the Sol Sherry Thrombosis Research Center at
TUSM, and Eric T. Choi, MD, Chief of Vascular and Endovascular Surgery
at Temple University Hospital, and Associate Professor of Surgery at
TUSM-- demonstrated that when caspase-1 was inhibited, VEGFR-2 activity
was enhanced and the cells' angiogenic function restored. The cells
successfully organized themselves into capillary-like structures in a
tube-formation assay designed to measure angiogenic potential.
Similar effects on angiogenesis were seen in caspase-1-deficient mice
with hyperlipidemia and hind-limb ischemia. Compared to hyperlipidemic
mice with normal caspase-1 expression, mice lacking the sensor molecule
had better blood flow and vessel growth in their ischemic limb.
"The findings describe the significance of the caspase-1 pathway to
post-ischemia revascularization," Dr. Yang said. "From a therapeutic
point of view, we want to try to trigger revascularization and make
existing vessels recover as soon as possible. The novel caspase-1
signaling pathway could have therapeutic potential in this area."
Dr. Yang next intends to figure out how caspase-1 modulates the
activities of endothelial cells and of bone marrow-derived stem cells,
which function in vascular repair. In research published earlier in
2015, he and colleagues discovered that caspase-1 activation weakened
the vascular repair activity of stem cells in hyperlipidemic mice. Those
findings could have implications for stem cell-based therapies for
ischemia.
Source:
Temple University Health System
