Activated protein C can protect against age-related cardiac ischemia and reperfusion injury

Date:
January 31, 2022
Source:
University of South Florida (USF Health)
Summary:
A preclinical study offers molecular insight into how activated
protein C (APC) may improve the tolerance of aging hearts to
reperfusion injury - - a potentially adverse effect of treatment
for ischemic heart disease


FULL STORY ==========================================================================
A University of South Florida Health (USF Health) preclinical study
offers molecular insight into how activated protein C (APC) may improve
aging patients' tolerance to reperfusion injury -- a potentially adverse
effect of treatment for ischemic heart disease.


==========================================================================
The research, published online Dec. 21 in Circulation Research, suggests
that drugs derived from APC may limit ischemia and reperfusion-induced
heart damage (reperfusion injury for short) and thereby help preserve
cardiac function in older hearts.

Advanced age is a major risk factor for ischemic heart disease, often
caused by a buildup of plaques in coronary arteries that narrows the
vessels and restricts the supply of oxygenated blood to the heart. This "hardening of the arteries" can eventually trigger a heart attack.

Blood thinners, clot-buster medications, and other drugs, as well as
procedures such as coronary artery bypass surgery and balloon angioplasty,
are commonly used to restore blood flow to oxygen-starved (ischemic)
heart muscle tissue.

Paradoxically, especially in older patients, these necessary
revascularization treatments can worsen cellular dysfunction and death
around the site already damaged by a heart attack, or coronary artery
disease. No effective treatments currently exist to prevent age-related reperfusion injury.

"Our research focuses on trying to determine why older hearts are at
greater risk for reperfusion injury than younger hearts," said lead
author Di Ren, PhD, a research associate in the Department of Surgery,
USF Health Morsani College of Medicine. "Our goal is to find targeted therapeutic strategies to help older people improve their resistance
to the pathological condition of ischemia and reperfusion stress."
"The preliminary evidence in this paper suggests that treatment with
activated protein C has the potential to strengthen the cardiac tolerance
of aging patients to reperfusion injury from surgery, minimally invasive procedures, or drugs, and (thereby) increase heart attack prevention
or survival," said the study's principal investigator Ji Li, PhD,
a professor of surgery at the USF Health Heart Institute.



==========================================================================
APC, a protein circulating in blood, has both anticoagulant (blood
clot prevention) and anti-inflammatory functions that can help protect
cells from disease and injury. Endothelial protein C receptor (EPCR)
-- located both on cells lining blood vessels and on the surface of
cell membranes, including heart muscle cells -- is associated with
increased APC production and regulates APC's subsequent cell signaling
(or cell communication).

In this mouse model study, the researchers analyzed how APC exerts cardiac protection during ischemia and reperfusion. The groups of mice observed included young and old "wild-type" mice with all their genes intact,
and young "knock-in" EPCR R84A/R84A mice genetically modified to make
their EPCR receptors incapable of interacting with the APC protein as
well as their wild- type littermates without the EPCR R84A/R84A mutation.

Naturally occurring APC or one of two laboratory-engineered APC
derivatives were administered to the mice with heart attack-induced
ischemia before reperfusion. One derivative (compound APC-2Cys)
selectively activated a signaling pathway to promote cell protection
without inhibiting blood clotting (coagulation). The other derivative
(compound APC-E170A) selectively triggered a signaling pathway promoting
only anticoagulation.

Among the team's key preclinical findings:
* The stress of Ischemia and reperfusion injury induced "shedding"
of EPCRs
in young and old wild-type mice -- that is, a greater number of
these receptors were cut from the heart muscle cell membrane and
then moved into the bloodstream. This EPCR shortage (deficiency)
in the heart can impair activated protein C signaling critical
for favorably regulating energy metabolism and anti-inflammatory
responses, preventing cell death, and stimulating other activities
needed to protect cardiac muscle cells.

* While the hearts of the old and young wild-type mice both showed
EPCR
shedding, older hearts experienced a more severe EPCR deficiency
and decline in APC signaling activity in response to reperfusion
injury. No APC signaling was detected in the EPCRR84A/R84A mice,
because APC was blocked from binding to the cell membrane receptor.

* Administering APC or its derivatives helped reduce heart damage
inflicted
by ischemia and reperfusion, particularly in the old mice. Digging
deeper, the researchers discovered that by stabilizing (maintaining)
EPCR on the cardiac cell membrane, APC strengthens the aging
heart's resistance both to heart attack-related ischemia and to
injury associated with restoring coronary artery blood flow.

* Furthermore, APC and the APC-2Cys signaling derivative, but not
the APC-
E170A anticoagulant-selective signaling (a potential bleeding risk),
helped preserve cardiac function. All cardioprotective effects
of APC were weaker in young mice in which EPCR was eliminated;
their hearts looked and performed like that of older mice.

* The researchers detailed how APC treatments improve cardiac
function by
regulating both acute (short-term) and chronic (longer-term)
metabolic pathways. They demonstrated that enzyme AMPK
(AMP-activated protein kinase) mediates an acute adaptive response
to cardiac stress immediately following heart attack, while enzyme
AKT (protein kinase B) regulates chronic metabolic adjustments to
reperfusion stress over time. APC treatment led to better enzyme
activity and more efficient energy balance needed to contract
cardiac muscle cells and pump blood from the heart to the rest of
the body.

"APC is beneficial for ischemia-reperfusion injury both in the acute
and chronic stages, so appropriate APC derivatives might be used both
as preventive and therapeutic drugs," Dr. Li said.

The USF Health Heart Institute researchers collaborated with scientists
from Scripps Research Institute, McMaster University (Canada), and the
Oklahoma Medical Research Foundation.

Their work was funded by grants from the National Institutes of Health,
both the NIGMS and NHLBI.

special promotion Explore the latest scientific research on sleep and
dreams in this free online course from New Scientist -- Sign_up_now_>>> ========================================================================== Story Source: Materials provided by
University_of_South_Florida_(USF_Health). Original written by Anne
DeLotto Baier. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Di Ren, Julia Fedorova, Kayla Davitt, Tran Ngoc Van Le, John
H. Griffin,
Patricia C. Liaw, Charles T. Esmon, Alireza R. Rezaie, Ji
Li. Activated Protein C Strengthens Cardiac Tolerance to Ischemic
Insults in Aging.

Circulation Research, 2022; 130 (2): 252 DOI: 10.1161/
CIRCRESAHA.121.319044 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220131100824.htm

--- up 8 weeks, 2 days, 7 hours, 13 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)