# RNA-Mediated Inter-Organelle Communication in Atherosclerosis

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2022 · $498,851

## Abstract

PROJECT ABSTRACT
Ischemic cardiovascular disease (CVD) is caused by atherosclerosis, a lipid-driven inflammatory disease
affecting the arteries, which can progress into vulnerable plaques and thrombotic occlusion. The precise
molecular mechanisms linking nutrient excess and hyperlipidemia to immune activation remains elusive and
the discovery of these mechanisms could lead to novel CVD therapeutics. An important primer for
inflammation in dyslipidemia is the chronic metabolic overloading and impairment of anabolic and
catabolic organelles. Reduction of organelle stress alleviates insulin resistance and atherosclerosis.
Recently, we showed that small molecule inhibitors of Inositol-requiring enzyme -1 (IRE1), a proximal ER
stress sensor, counteract atherosclerosis progression. The ER membranes also serve as a nucleation site
for RNA-induced silencing complex (RISC), and we made the striking discovery that IRE1 kinase
phosphorylates the double stranded RNA-binding protein, the protein activator of the protein kinase R
(PACT), that associates with RISC. We found lipid stress induces IRE1 to phosphorylate PACT, which
suppresses mitochondrial biogenesis (mito-biogenesis), in part by controlling a miRNA (miR)-181c.
Homeostatic mechanisms such as mitophagy (to remove) or mito-biogenesis (to replenish) the malfunctioning
mitochondria can counteract inflammation and also operate in atherosclerotic plaque cells. Aberrant activation
of IRE1-PACT signaling by lipids block mito-biogenesis and propagate mitochondrial oxidative (MOX) stress
and inflammation, indicating inhibition of this pathological signaling could counteract atherosclerosis. PACT
is proximal to a locus on human chromosome 2 that is linked to premature coronary artery disease and
plasma HDL-C levels. PACT expression is induced during atherosclerosis progression and reduced during
regression in mice. We hypothesize that suppressing IRE1-PACT signaling will promote mito-biogenesis
and counteract inflammation and atherosclerosis. We will elucidate how PACT regulates mito-biogenesis by
discovering PACT’s miR target(s) and their RNA targets that are relevant to mito-biogenesis regulation. We
discovered miR-181c is one of these PACT targets that blocks mito-biogenesis. We will directly investigate the
impact of PACT and miR-181c on hyperlipidemia-induced mito-biogenesis, inflammation and atherosclerosis
in vivo. Based on the discovered targets (for miR-181c and others) we will develop a more specific
therapeutic targeting approach (using Locked Nucleic Acid-Target-Site Blockers) to ablate miR and target
interaction in atherosclerotic mice. The successful completion of these studies will help define an
unprecedented mechanism of immune-metabolic crosstalk between ER and mitochondria by which
hyperlipidemia can promote MOX stress, inflammation and atherosclerosis. Understanding the intrinsic
operation of this RNA-mediated inter-organelle communication during atherogenesis could pave the
way for novel ...

## Key facts

- **NIH application ID:** 10428386
- **Project number:** 5R01HL149972-03
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Moshe Arditi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $498,851
- **Award type:** 5
- **Project period:** 2020-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10428386

## Citation

> US National Institutes of Health, RePORTER application 10428386, RNA-Mediated Inter-Organelle Communication in Atherosclerosis (5R01HL149972-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10428386. Licensed CC0.

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