# PCSK9-A novel target for the treatment of myocardial ischemia

> **NIH VA I01** · CENTRAL ARKANSAS VETERANS HLTHCARE SYS · 2020 · —

## Abstract

Mainly expressed in liver, kidney and small intestine, the enzyme proprotein convertase subtilisin/kexin
type 9 (PCSK9) binds to the low-density lipoprotein-cholesterol receptor (LDLr), and causes degradation
of LDLs. Although not proven, it has been suggested that these agents may reduce cardiovascular
events. Recent work from our group shows that besides the liver, kidney and small intestine,
cardiomyocytes also express PCSK9. The secretion of PCSK9 increases during ischemia by >10 fold.
PCSK9 expression is maximal in the region adjacent to the infarcted area (border zone). Cardiomyocytes
in the border zone also exhibit intense inflammation and autophagy. Other recent work in our
laboratory suggests that PCSK9 secretion may regulate inflammation and autophagy. Based on these
new findings, we wish to critically examine the role of myocardial PCSK9 in ischemia, an issue not
previously studied. The 2 major aims of the grant proposal are:
Aim 1: To examine the role of PCSK9 in the determination of infarct size and cardiac function.
Approach: These studies will be done in a mouse model of permanent left coronary artery (LCA)]
ligation. Studies will be performed in wild-type C57BL/6 and PCSK-/- mice. PCSK9 expression,
inflammation (with emphasis on infiltration of tissue injurious CCR2+Ly6Chigh monocytes and
neutrophils) and autophagy along with infarct size and cardiac function (echocardiography) will be
measured at different time points. Molecular biology studies, histology and immunohistochemistry will
be performed in different regions of the heart. To determine the role of inflammation in PCSK9 release
and its effects, parallel studies will be performed in TNFα-/- mice and IL-1β-/- mice. Lastly, to confirm
the role of PCSK9 in ischemic injury, studies will be performed in mice with selective PCSK9 deletion in
the heart. Impact: These in vivo studies will clarify the role of PCSK9 in determination of infarct size and
cardiac function/remodeling. Further, these studies will reveal the role of inflammation in the induction
of PCSK9 secretion during chronic ischemia.
Aim 2: To examine mechanisms underlying PCSK9’s effects on the heart during ischemia. Approach: To
study the complex interaction between PCSK9, inflammation and autophagy during ischemia, primary
mouse cardiomyocytes will be exposed to varying periods of hypoxia (in vitro studies). We will study the
impact of hypoxia-induced PCSK9 release on leukocyte migration, mitochondrial ROS generation and
mitochondrial DNA damage and autophagy signals. Impact of PCSK9 (along with inflammatory signals)
on the generation of collagen (in fibroblasts) will also be studied. Impact: These studies will reveal the
mechanisms by which PCSK9 influences inflammation and autophagy, and subsequently cardiac
remodeling during chronic myocardial ischemia.
Innovation and Significance: PCSK9 inhibition by lowering LDL-C may significantly influences
atherogenesis and cardiovascular events. We believe that the propos...

## Key facts

- **NIH application ID:** 9896662
- **Project number:** 5I01BX000282-10
- **Recipient organization:** CENTRAL ARKANSAS VETERANS HLTHCARE SYS
- **Principal Investigator:** JAWAHAR L MEHTA
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2009-10-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9896662

## Citation

> US National Institutes of Health, RePORTER application 9896662, PCSK9-A novel target for the treatment of myocardial ischemia (5I01BX000282-10). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9896662. Licensed CC0.

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