Abstract 19721: ATF6 is Required for ANP Secretion From the Heart
Introduction: Atrial natriuretic peptide (ANP) is a potent depressor hormone synthesized and stored in the heart in secretory granules of atrial myocytes as a biologically inactive precursor, pro-ANP. Hemodynamic stress and neurohormones, such as the α-adrenergic receptor agonist, phenylephrine (PE) stimulate coordinate secretion and proteolytic cleavage of pro-ANP to its bioactive form, ANP, which promotes renal salt excretion and vasodilation restoring blood pressure. Endoplasmic reticulum (ER) protein folding is critical in all endocrine cells, such as the pancreas because insulin synthesis and folding in the ER of pancreatic β-cells is required for secretion of bioactive insulin. As important as atrial ANP is for normal cardiovascular physiology, ER protein folding and the role of the integral transcription factor, ATF6, which is activated in response to ER protein misfolding in the formation and secretion of bioactive ANP has not been previously examined.
Hypothesis: ATF6 is required for optimal secretion of ANP from the atria.
Methods: To address this gap in our knowledge, we knocked down ATF6 in primary cultured neonatal rat atrial myocytes (NRAMs) using siRNA and measured ANP expression and secretion basally and in response to PE. We also compared ANP secretion from wild-type (WT) mice and ATF6 knockout (ATF6 KO) mice in an ex vivo Langendorff model of the isolated perfused heart. Additionally, we subjected the WT and ATF6 KO mice to a salt-stress chow diet and compared their responsiveness to circulatory sodium overload and hypertension as well as the circulating ANP concentrations in blood plasma.
Results: ATF6 knockdown in NRAMs significantly impaired basal and PE-stimulated ANP secretion. Similarly, in the ex vivo isolated perfused heart model, less ANP was detected in the effluent of ATF6 KO hearts, compared to that of WT hearts. Additionally, ATF6 KO mice demonstrated a greater sensitivity to sodium overload, in vivo, as evidenced by increased blood pressure and pathological cardiac hypertrophy.
Conclusions: As ANP is secreted in a regulated manner in response to a stimulus, we posit that ATF6 is required for adequate folding, trafficking, and secretion of biologically active ANP from the endocrine heart.
- Atrial natriuretic peptide (factor)
- Atrial function
- Antihypertensive agents
- Cell physiology
Author Disclosures: E.A. Blackwood: None. J. Jin: None. K. Azizi: None. A. Arrieta: None. D. Thuerauf: None. C. Glembotski: None.
- © 2016 by American Heart Association, Inc.