# Roles for endoplasmic reticulum associated degradation (ERAD) in Myocardial Proteostasis

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2024 · $723,894

## Abstract

Proteostasis comprises the processes governing the life cycle of proteins from synthesis to degradation.
Imbalanced proteostasis contributes to numerous pathologies, including those affecting the heart. Proteostasis
in the sarco/endoplasmic reticulum (ER) of cardiac myocytes is important since proteins involved in contractile
Ca handling, as well as receptors and secreted proteins, are synthesized on ER-bound ribosomes. We found
that cardiac pathology imbalances ER proteostasis, causing ER stress and misfolded proteins that must be
degraded to avoid toxicity. This proposal concerns one such degradation process, ER associated protein
degradation (ERAD), which is the mechanism responsible for proteasome-mediated degradation of ER
proteins. We found that in mice cardiac ischemia/reperfusion (I/R) increases ROS and activates the ER stress
response, which induces several previously uncharacterized antioxidant proteins, including the trans-ER
membrane selenoprotein, Vimp, which has not been studied in the ischemic heart. We found that Vimp
knockdown in mice increased I/R-generated ROS and infarct size in in vivo I/R, consistent with a role for Vimp
as an antioxidant. In addition to its antioxidant activity, Vimp has been shown in model cell lines to be important
for assembly of the ERAD complex, the function of which is not known to require antioxidants or Se. Vimp
overexpression in cultured cardiac myocytes increased ERAD, consistent with Vimp’s function as a key regulator
of ERAD in the heart. Our hypothesis is that Vimp mitigates ROS and misfolded protein accumulation, both of
which protect against I/R damage. Moreover, the unique dual roles of Vimp are mechanistically linked to the
antioxidant function of its Se and the protein degradation function of its ERAD domain. Finally, endogenous
proteins in the heart are degraded by ERAD as part of their life cycle, which is essential for balancing proteostasis
and optimizing heart function. Our specific aims are to: 1- determine the effects of AAV9-sh-RNA-mediated
knockdown of endogenous Vimp, which is very effective in vivo, on cardiac structure and function, infarct size
and remodeling, as well as ROS, ERAD and molecular sensors of cardiac pathology and ER protein misfolding
in mice subjected to I/R, 2- mechanistically dissect roles for the Se and the ERAD-enabling domain of Vimp
using AAV9 encoding wild type Vimp (Vimp-WT), Vimp lacking Se (Vimp-Se), and Vimp with a mutated,
dysfunctional ERAD domain (Vimp-ERAD), allof which we have already prepared, in mice subjected to I/R, and 3-
use three complementary approaches to examine how ERAD affects endogenous proteins in the mouse heart,
in vivo, investigating 1- ERAD-mediated degradation of Serca2a, 2- ER proteome dynamics using ER-targeted
proximity biotin labeling and quantitative proteomics, and 3- ER proteome dynamics using stable isotope labeling
mass spectrometry. In terms of relevance to heart disease or significance, our concept that ERAD is criti...

## Key facts

- **NIH application ID:** 10939599
- **Project number:** 1R01HL174576-01
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Chris Glembotski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $723,894
- **Award type:** 1
- **Project period:** 2024-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10939599

## Citation

> US National Institutes of Health, RePORTER application 10939599, Roles for endoplasmic reticulum associated degradation (ERAD) in Myocardial Proteostasis (1R01HL174576-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10939599. Licensed CC0.

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