Dynamics of Annexin A6 Modulates Atrial Natriuretic Peptide Driven Counter-Hypertrophic Responses in Cardiomyocytes

Deregulations in pathways controlling cell-size are prominent in maladaptive cardiac hypertrophy. Here, we show annexin A6 (Anxa6) to be a crucial regulator of counter-hypertrophic signaling in cardiomyocytes. Adrenergic agonist phenylephrine (PE) increased cell-size of H9c2 cardiomyocytes with characteristics of hypertrophic transformation and remodeled cytosolic Anxa6 distribution with elevated expression. Controlled up-regulation of Anxa6 protected the cells against PE but knockdown augmented the hypertrophic responses albeit abrogated juxtanuclear accumulation of secretory proANP granules (proANP-SG), a hypertrophic marker with counter-hypertrophic functions, without affecting proANP transcript levels. PE treatment also altered dynamics of Anxa6 on a temporal scale that paralleled its progressive and kinetic association with proANP anterograde translocation. Mutagenesis studies mapped the structural features necessary for de facto localization of Anxa6 and its relationship with proANP. Anxa6 mutants that failed to associate with proANP because of domain deletion or defective localization abrogated proANP-mediated protection against PE that could be rescued, at least partially, by full-length Anxa6. Elevating intracellular Ca2+ also induced Anxa6-proANP association, which were abolished by Ca2+ chelation. Thus, present study reports a triggering function of Anxa6 that regulates proANP vesicular traffic, thereby mediating anti-hypertrophic signaling in cardiomyocytes.View Large Image | View Hi-Res Image | Download PowerPoint Slide