# Harnessing the Adaptive ER Stress Response in Myocardial Ischemia

> **NIH NIH R01** · SAN DIEGO STATE UNIVERSITY · 2020 · $26,318

## Abstract

Project Summary
Myocardial ischemia causes ER stress and potentially lethal ER protein misfolding. The adaptive ER stress
response restores ER protein folding and fosters myocyte survival. If this process is not sufficient to restore ER
protein folding, the ensuing maladaptive ER stress response leads to myocyte death. To survive the hypoxic
environment in tumors, cancer cells have evolved an exaggerated adaptive ER stress response, mediated
partly by the transcription factor, ATF6, which is activated by ER stress. Compared to cancer cells, normal cells
have relatively little ATF6 and a weak adaptive ER stress response. Our preliminary data showed that ATF6
deletion increased infarct size and decreased function in mouse hearts subjected to myocardial infarction. The
objective of the proposed research is to examine the molecular mechanism of ATF6 function in the heart,
which will reveal new information needed to develop novel therapies for ischemic heart disease based on
harnessing the adaptive ER stress response in the heart. In our previous studies, we were surprised to find
that activated ATF6 is rapidly degraded; this degraded-when-active property suggests that strict regulation of
the level of ATF6 and the genes it regulates, must have functional significance; however, this significance has
not been examined. Our hypotheses are as follows: 1- Endogenous ATF6 adaptively decreases apoptosis and
infarct size upon ischemia, which improves post-ischemia myocardial recovery. 2- ATF6 is degraded when
active because short-term ATF6 activation is adaptive, while long-term ATF6 activation is maladaptive. 3-
Activation of endogenous ATF6 with small molecule activators is adaptive, and because it is reversible, we can
regulate dose and time to maximize adaptive and minimize maladaptive effects of ATF6 activation to optimize
therapeutic potential. These three hypotheses will be addressed by the following corresponding Specific Aims:
1- To assess the effects of endogenous ATF6 deletion on cardiac structure and function in an MI model of
heart failure using ATF6 knockout (KO) mice. 2- To use AAV9-mediated gene transfer of forms of ATF6 that
exhibit a range of degraded-when-active properties into ATF6 KO mice, then assess the effects of these forms
of ATF6 on cardiac structure and function in an MI model of heart failure. 3- To determine the effects of novel
small molecule activators of endogenous ATF6 on the viability and on ER stress signaling, initially in isolated
cardiac myocytes and then and in mice, in vivo.

## Key facts

- **NIH application ID:** 9924642
- **Project number:** 5R01HL135893-04
- **Recipient organization:** SAN DIEGO STATE UNIVERSITY
- **Principal Investigator:** Chris Glembotski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $26,318
- **Award type:** 5
- **Project period:** 2017-06-01 → 2020-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9924642

## Citation

> US National Institutes of Health, RePORTER application 9924642, Harnessing the Adaptive ER Stress Response in Myocardial Ischemia (5R01HL135893-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9924642. Licensed CC0.

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