HERP Regulates Cardiomyocyte Hypertrophy By Controlling Inositol Triphosphate Receptor

N Torrealba1, C Fernandez1, F Paredes1, Z Pedrozo1, S Lavandero1,2. 1Advanced Center for Chronic Diseases (ACCDiS) and Center for Molecular Studies of the Cell (CEMC), Faculty of Chemical and Pharmaceutical Sciences & Faculty of Medicine, Universidad de Chile, Santiago, Chile, 2Department of Internal Medicine, Southwestern Medical Center, University of Texas, Dallas, Texas, USA

HERP is an endoplasmic reticulum (ER) membrane protein linked to ER-associated degradation. HERP has also shown to regulate Ca2+ homeostasis trough the degradation of the inositol triphosphate receptor (IP3R) during ER stress in a neuronal model. Although HERP has been found in the heart, its function remains still not understood. Pathological cardiac hypertrophy can be triggered by a chronic activation of the sympathetic system via the activation of the α1-adrenergic receptor/IP3R/Ca2+ signaling pathway. Moreover, IP3R is overexpressed during cardiac hypertrophy. Thus, we are investigating whether HERP prevents the development of cardiomyocyte hypertrophy by regulating IP3R protein levels.

To this end, neonatal cultured rat cardiomyocytes were treated with a siRNA against HERP (Sigma SASI_Rn01_00057861) in the absence or presence of the hypertrophic agonist norepinephrine (NE 10 uM) as a positive control. Our data showed that NE increases HERP protein levels (1.8 fold increase after 24 hours incubation, p <0.05). The latter result might imply that HERP either acts as a compensatory mechanism against hypertrophy or that it contributes to the hypertrophic process down-stream from NE. Interestingly, HERP down-regulation by siRNA stimulated cardiomyocyte hypertrophy, increasing sarcomerization (from 5% to 80%, p <0.05), cell perimeter (by 50%, p <0.05) and area (by 60%, p <0.05) as well as beta-myosin heavy chain levels (1.5 fold increase, p <0.05) in a similar manner to that observed with NE. Also, protein levels of IP3R increased after HERP knock-down (1.6 fold increase, p <0.05), an effect that could be triggering the cardiomyocyte hypertrophic phenotype. Therefore, the increase in HERP protein levels seen after NE incubation appears to be a compensatory mechanism rather than a pro-hypertrophic one. Taken together, this novel data supports a new role for HERP in cardiac pathophysiology and establishes a new potential therapeutic target for the treatment of cardiac diseases.

Supported by ACT 1111 (SL), FONDAP 15130011 (SL), FONDECYT 1120212 (SL), CONICYT PhD fellowship 21120416 (NT).