# Effect of CTHRC1 on endothelial cell survival after acute ischemia

> **NIH NIH R01** · MAINEHEALTH · 2022 · $534,576

## Abstract

Abstract
In previous studies we have demonstrated that CTHRC1 (Collagen Triple Helix Repeat Containing 1), a factor
discovered in our laboratory, is constitutively expressed only in brain and bone and not in other tissues during
adulthood. However, CTHRC1 is highly expressed in activated fibroblasts and interstitial cells of tissues
undergoing remodeling and repair. We discovered that CTHRC1 is a circulating factor but only approximately
30% of healthy human subjects have detectable levels of CTHRC1 in plasma, ranging in concentration from
low pg/ml to almost 100ng/ml. Similar to most humans, circulating levels of CTHRC1 are not detectable in mice
and rats and forced transgenic overexpression of CTHRC1 under Pdgfrb promoter control does also not result
in detectable CTHRC1 plasma levels. Thus there are two pools of CTHRC1; one that is generated locally in
tissues undergoing repair requiring >48 hours to be available, and a second pool of circulating CTHRC1
available at all times and found only in a minority of human subjects. The significance of circulating CTHRC1
for the cardiovascular system became apparent when we obtained plasma samples from patients experiencing
cardiac arrest, a condition with approximately 50% mortality. High CTHRC1 levels (≥0.75ng/ml) are associated
with substantially higher survival rates in humans experiencing cardiac arrest. While CTHRC1 is not expressed
in the adult heart, it is highly induced in fibroblasts activated in response to myocardial infarction. To test the
role of CTHRC1 in acute ischemic injury, we performed coronary artery ligation in Cthrc1 null mice and Cthrc1
transgenic mice on the Cthrc1 null background with physiologically relevant CTHRC1 plasma levels in the
ng/ml range found in humans. Strikingly, 70% of Cthrc1 null mice died 3-4 days after the ischemic injury
whereas all transgenic mice survived. With the goal of identifying the mechanism for this dramatic finding we
performed in vitro studies and found that CTHRC1 promotes cell survival in variety of cell types including
endothelial cells. Complete metabolic monitoring revealed that Cthrc1 null mice have increased energy
expenditure at rest and analysis of cell metabolism in vitro revealed that in the presence of CTHRC1
mitochondrial respiration is significantly increased whereas glycolysis is reduced, leading us to hypothesize
that CTHRC1 functions as a mediator of metabolic efficiency. Overall, this proposal will test the hypothesis that
CTHRC1 functions as a mediator of cell survival under conditions of cell stress by increasing metabolic
efficiency, which in turn protects from the deadly consequences of acute ischemic injury. We will determine if
increasing circulating- or CTHRC1 tissue levels provides cardiovascular protection by limiting the deleterious
consequences of myocardial ischemia. Using genetic mouse models and in vitro approaches the underlying
mechanism of action will be identified, and this will provide the foundation for novel ...

## Key facts

- **NIH application ID:** 10312789
- **Project number:** 5R01HL146504-03
- **Recipient organization:** MAINEHEALTH
- **Principal Investigator:** VOLKHARD LINDNER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $534,576
- **Award type:** 5
- **Project period:** 2019-12-20 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10312789

## Citation

> US National Institutes of Health, RePORTER application 10312789, Effect of CTHRC1 on endothelial cell survival after acute ischemia (5R01HL146504-03). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10312789. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*