# Flow responsive endothelial Pnpt1: an exoribonuclease that regulates mitochondrial function and vascular disease

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2020 · $438,002

## Abstract

This proposal aims to delineate molecular mechanisms that link laminar flow mediated signaling with gene
expression, mitochondrial homeostasis and endothelial cell (EC) function. Carotid intima-media thickening
(IMT) is caused by intima growth, and is a significant risk factor for cardiovascular diseases (CVD). Intima
growth is mediated by EC dysfunction, vascular smooth muscle cell (VSMC) growth as well as inflammatory
cell accumulation and activation. These pathological processes are stimulated by a disturbed flow pattern (d-
flow), while being minimized by steady s-flow. Using congenic mouse strains, we identified a QTL for intima in
C3H/F (no intima) and SJL (high intima) mice on chromosome 11 (Im2) that overlapped with a vascular
inflammation QTL. Transcriptomic and bioinformatic analyses revealed significant differences in inflammation,
cell cycle and RNA degradation. Using KEGG pathway analysis, a focus on genes in Im2 with polymorphisms
that were differentially expressed between C3H/F and SJL identified a single gene: polyribonucleotide
nucleotidyltransferase 1 (Pnpt1), a 3'-5' exoribonuclease that is required for import and processing of RNA in
mitochondria. High level Pnpt1 expression correlated with decreased intima growth and inflammation in the
carotid ligation model suggesting it was protective. The goal of this proposal is to understand how Pnpt1
restricts inflammation and atherosclerosis, focusing on novel transcriptional programs and mechanisms that
link d-flow-mediated signaling through mitochondrial homeostasis, mitophagy/autophagy and cellular RNA
processing pathways to EC dysfunction and CVD. While intima growth is primarily due to proliferation of VSMC
and fibroblast-like cells, we focused on d-flow-mediated effects on EC because we believe these signals are
initiating events, and are likely more specific and better therapeutic targets. We hypothesize that Pnpt1 is a
mechanoresponsive enzyme that is critical to mitochondrial homeostasis and acts as a negative regulator of
vascular inflammation and intima growth, thereby limiting CVD. Exciting preliminary data in support of the
hypothesis include 1) inducible EC-specific Cre-loxP Pnpt1 mice that exhibit increased intima formation upon
loss of Pnpt1; 2) RNA-Seq analyses of altered Pnpt1 expression under different flow patterns identified a novel
and significant role for the TFAP2b/c transcription factor; 3) d-flow inhibited Pnpt1 function in EC; 4) Pnpt1
expression regulated EC inflammatory and apoptotic signaling both in vivo and in vitro and 5) Pnpt1 deficiency
exacerbated mitochondrial-stress, as measured by ROS generation and autophagy. Proposed experiments will
study changes in vascular remodeling and atherosclerosis in transgenic mouse models; determine the
transcriptional program regulated by Pnpt1 focusing on the TFAP2b/c transcription factor; and the mechanisms
by which flow regulates Pnpt1 function assayed by expression and enzyme activity. This proposal will
charact...

## Key facts

- **NIH application ID:** 9850623
- **Project number:** 5R01HL140958-03
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Bradford C Berk
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $438,002
- **Award type:** 5
- **Project period:** 2018-01-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850623

## Citation

> US National Institutes of Health, RePORTER application 9850623, Flow responsive endothelial Pnpt1: an exoribonuclease that regulates mitochondrial function and vascular disease (5R01HL140958-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9850623. Licensed CC0.

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