Abstract 17012: Mesencephalic Astrocyte-Derived Neurotrophic Factor is an Endoplasmic Reticulum Stress-Inducible Protein with Novel Roles as a Regulator of Cardiac Myocyte Growth
Most secreted and membrane proteins, including hormones, receptors, growth factors, ion channels, and calcium-handling proteins are made in the sarco/endoplasmic reticulum (SR/ER) of cardiac myocytes. Many forms of heart disease cause ER stress, leading to the misfolding of proteins made in the SR/ER and subsequent activation of the unfolded protein response (UPR). A major feature of the UPR is a genetic reprogramming that is designed to relieve misfolded protein toxicity in the ER; this adaptive UPR has not been well studied in the heart. Our transcriptome analysis of a transgenic mouse model in which the adaptive UPR can be conditionally activated in cardiac myocytes showed that the recently discovered ER-resident protein, mesencephalic astrocyte-derived neurotrophic factor (MANF) was upregulated. MANF is a ubiquitously expressed, 158 amino acid protein that is not structurally related to any other protein. Moreover, the function of MANF is not well studied. We showed that MANF protects cardiac myocytes and mouse hearts from ischemia/reperfusion injury. We hypothesized that this protection is a result of a critical role for MANF in the adaptive UPR. To address this hypothesis, we studied the effects of altering MANF levels in HEK293 cells, neonatal rat ventricular myocytes (NRVM), and mouse hearts. MANF knockdown in cultured cells using siRNA resulted in an exaggerated UPR, as evidenced by upregulation of numerous proteins involved in the canonical ER stress response. Unexpectedly, MANF knockdown increased the size of both HEK293 cells and NRVM. To investigate the function of MANF in the heart, in vivo, we generated a mouse model in which a microRNA targeted to MANF (miMANF) is expressed in a cardiac-specific manner and decreases MANF levels by 80% in the heart. Adult miMANF mice showed an 11% increase in heart weight/tibia length and an unexpected enhancement of cardiac function, characterized by a 10% increase in fractional shortening. MANF knockdown in mouse hearts did not affect cardiac hypertrophy induced by angiotensin II administration or transaortic constriction-induced pressure overload. These results suggest that MANF is an adaptive UPR-inducible ER-resident protein and a novel regulator of cardiac myocyte and heart growth.
Author Disclosures: W.T. Stauffer: None. B. Bailey: None. A. Arrieta: None. S. Doroudgar: None. C.C. Glembotski: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.