Annexin A4 Deficient Ventricular Myocytes Display Advanced Hypertrophy and Electrical Remodeling With Chronic...

Annexin A4 (A4) is a negative modulator of adenylyl cyclase type 5 (AC5) with increased expression in failing human hearts. Here, we investigated whether A4 deficiency contributes to cardiac electrical and structural remodeling induced by chronic stimulation of β-adrenergic receptors (βAR). A4-deficient mice (gene trapped, GT) and wild-type (WT) were infused for 7 days with isoprenaline (ISO) or NaCl as control. Myocytes of ISO-treated GT (GT_ISO) displayed more hypertrophy, increased action potential duration, reduced K⁺-current I_to, preserved L-type Ca²⁺ current I_CaL with a negative shift of voltage dependence of activation, in line with increased AC/cAMP/PKA signaling, and increased NCX1 versus WT_ISO. At the molecular level, mRNA levels for Kcnd3, Kcnip2, Cacna1c decreased at unchanged protein levels of Kv4.2, Kv4.3, KChIP2, α1C, independent of genotype, suggesting posttranslational modifications of the channels underlying I_to and I_CaL. Chronic ISO-induced βAR desensitization and redox stress were confirmed by decreased cAMP production and lower mRNA levels of Adrb1, Adcy5/6, and Sod2, and reduced response to acute ISO, with no additional genotype-dependent effects on calcium handling or contractility. Nevertheless, GT_ISO cardiomyocytes retained a greater cAMP response to acute ISO, in line with AC5 disinhibition and preserved β2AR and Gαs/i, suggesting genotype-dependent differences in β-adrenergic signaling under stress. mRNA levels of Anxa4 were increased in hypertrophied WT_ISO vs. normal WT_NaCl hearts, supporting a protective role for A4. Overall, the advanced remodeling in A4-deficient myocytes detected in response to chronic βAR stimulation proposes using A4 peptide as a therapeutic tool to prevent the progression of cardiac electrical remodeling.