Elevated MAOA impairs intracellular β 1 ‐adrenegic signaling and myocardial contractility in heart failure

Rationale: We recently identified a pool of β 1 ARs at the sarcoplasmic reticulum (SR) senses cytosolic catecholamines and promotes cardiac contractility. Monoamine oxidase A (MAOA), the major enzyme metabolizing myocardial catecholamines is upregulated in heart failure (HF) together with blunted β 1 AR signaling. However, the regulation of intracellular β 1 ARs signaling in HF remains unknown. Objective To uncover the role of MAOA in the spatiotemporal regulation of intracellular β 1 AR signaling and cardiac contractility. Methods and Results Echocardiogram analysis showed that cardiac‐specific deletion (cKO) or pharmacological inhibition of MAOA did not affect the baseline cardiac output but significantly amplified the inotropy of catecholamine (epinephrine) in vivo . Enzyme immunoassay revealed elevated catecholamine concentrations and cAMP/PKA activities in MAOA‐cKO mice hearts compared with their flox/flox (FF) littermates. We measured the subcellular‐localized β 1 AR in living cardiomyocytes using PKA biosensors targeted at SR or plasma membrane (PM). Compared with FF cardiomyocytes, MAOA‐cKO exhibited an increased PKA activity at SR, but not PM upon epinephrine stimulation. Consistently, phosphorylation of phospholamban (PLB), a major target of SR‐localized β 1 AR signals, was enhanced by MAOA‐cKO. More importantly, deleting MAOA increased the response of calcium transients and contractility to epinephrine. Blocking the entry of catecholamines by organic cation transporter 3 (OCT3) inhibitor abolished the differential effects in MAOA‐cKO vs FF. Similarly, the effect of MAOA‐cKO on intracellular β1AR/PKA/PLB signaling and cardiac excitation‐contraction coupling (EC‐coupling) was recapitulated by pharmacological inhibition of MAOA. In contrast, overexpression of MAOA in cardiomyocytes suppressed epinephrine‐induced PKA activation at the SR, PLB phosphorylation and contractility. Furthermore, the increased expression of MAOA in failing cardiomyocytes suppressed activation of intracellular β 1 AR and attenuated PKA phosphorylation of PLB and inotropic responses. Inhibition of MAOA restored intracellular β 1 AR signaling and EC coupling in failing cardiomyocytes, and rescued the inotropy response in HF mice. Conclusion MAOA modulates catecholamine‐promoted EC coupling via tuning the intracellular β1AR signaling and PKA phosphorylation of PLB. Inhibition of MAOA restores β1AR/PKA signaling at the SR and cardiac contractility in HF.