# The Adaptive Cardiac Sensor, ATF6, Regulates ANP Secretion and Decreases Hypertensive Stress

> **NIH NIH F31** · SAN DIEGO STATE UNIVERSITY · 2020 · $4,748

## Abstract

Project Summary
 This research proposes a novel and innovative link between the ER stress response (ERSR) and
hypertension in atrial myocytes. During pressure-overload and ischemia the synthesis and folding of proteins in
the ER is perturbed leading to ER stress in the cardiac myocyte, and potential cardiac dysfunction. When ER
protein folding is impaired, hundreds of genes encoding the ER protein folding machinery are induced by the
primary adaptive cardiac sensor, ATF6. Increased blood pressure and plasma sodium stimulate the secretion
and cleavage of pro-ANP to form the adaptive cardiac effector, ANP, which promotes salt excretion and
vasodilation, which homeostatically restore blood pressure. Recently, we identified 381 genes that were
specifically induced by ATF6 in the mouse heart. Of the genes identified, 30 encode proteins known to be
secreted by the conventional secretory pathway. Further analysis revealed additional genes encoding proteins
that are essential elements of the secretory pathway. One such protein, SNAP23, is required for secretory
granule exocytosis in neurons and to co-localize with ANP-containing secretory granules in the atria. The
novelty of this finding lies in the fact, that although global protein synthesis and secretion are down-regulated
during the ERSR, expression of proteins required for the regulated secretion of adaptive proteins through the
conventional secretory pathway is increased. The hypothesis addressed in this proposal is that the adaptive
cardiac sensor, ATF6 is required for the proper secretion of adaptive cardiac effector, ANP from atrial
myocytes, and that a robust ATF6-ANP axis is required for cardiovascular homeostasis. To address this
hypothesis, the specific aims are to 1) examine how ATF6 gain- and loss-of-function affect ANP secretion from
cultured rat and mouse atrial myocytes, and from the mouse heart, and 2) assess the effects of ATF6 gain-
and loss-of-function in a clinically relevant mouse model of hypernatremia-induced hypertension. These aims
will be achieved using cultured cardiac myocytes for mechanistic studies and in the mouse heart using a novel
ATF6-floxed mouse line to conditional knockout the gene in cardiac myocytes and a selective small molecule
activator of endogenous ATF6. In addition to determining the importance of the ATF6-ANP axis, this study will
assess the viability of ATF6 as a potential therapeutic target for ANP-based imbalances in hypertensive stress
and cardiovascular homeostasis.

## Key facts

- **NIH application ID:** 9882517
- **Project number:** 5F31HL140850-03
- **Recipient organization:** SAN DIEGO STATE UNIVERSITY
- **Principal Investigator:** Erik Blackwood
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $4,748
- **Award type:** 5
- **Project period:** 2018-03-01 → 2020-04-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9882517

## Citation

> US National Institutes of Health, RePORTER application 9882517, The Adaptive Cardiac Sensor, ATF6, Regulates ANP Secretion and Decreases Hypertensive Stress (5F31HL140850-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9882517. Licensed CC0.

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