Introduction: Sarco/endoplasmic reticulum (SR/ER) integrity is crucial for cardiac function. Cardiac diseases induce ER protein misfolding and activate ER stress. ATF6, an ER-transmembrane protein, is a sensor of ER protein misfolding. Upon ER stress, ATF6 becomes a transcription factor that induces adaptive proteins that restore ER protein folding capacity. We previously showed that several ATF6-inducible gene products protect from progression towards heart failure during pathological remodeling. However, the molecular mechanisms of this protection are unknown.
Hypothesis: ATF6 is required for balancing protein quantity and quality during cardiac growth.
Methods: ATF6 activation and target gene induction was assessed in neonatal and adult rat ventricular myocytes during growth stimulation by phenylephrine or isoproterenol. Additionally, the effects of ATF6 knockdown on the cardiomyocyte growth response was analyzed. To examine the role of ATF6 in cardiac growth, in vivo, ATF6 knockout (KO) and wild type (WT) mice were treated with isoproterenol in osmotic minipumps to induce a hypertrophic response to β-adrenergic stimulation. Minipumps with saline in WT and ATF6 KO mice served as controls.
Results: In neonatal rat ventricular myocytes, ATF6 knockdown decreased cell size and phenylephrine-induced growth. Increased protein synthesis during growth led to the increased expression of ATF6-induced chaperones in adult rat cardiac myocytes. Compared to WT, hearts from isoproterenol-treated ATF6 KO mice exhibited reduced cardiac hypertrophy, as assessed by heart weight-to-body weight ratios and myocyte cross-sectional area. Echocardiography revealed significantly decreased fractional shortening in hearts from isoproterenol-treated ATF6 KO, compared to WT mice, suggesting that ATF6 contributes to the cardiac growth seen in isoproterenol-induced cardiac hypertrophy. RNA-seq and molecular signaling analyses revealed increased expression of pathology-associated genes in the absence of ventricular hypertrophy in the hearts of ATF6 KO mice treated with isoproterenol.
Conclusion: ATF6 protects from pathological remodeling during cardiac hypertrophy by coupling protein quality with protein quantity control.