Galectin-3-centered paracrine network mediates cardiac inflammation and fibrosis upon beta-adrenergic insult

Rapid over-activation of beta-adrenergic receptors (beta-AR) following acute stress initiates cardiac inflammation and injury by activating interleukin-18 (IL-18), however, the process of inflammation cascades has not been fully illustrated. The present study aimed to determine the mechanisms of cardiac inflammatory amplification following acute sympathetic activation. With bioinformatics analysis, galectin-3 was identified as a potential key downstream effector of beta-AR and IL-18 activation. The serum level of galectin-3 was positively correlated with norepinephrine or IL-18 in patients with chest pain. In the heart of mice treated with beta-AR agonist isoproterenol (ISO, 5 mg kg(-1)), galectin-3 expression was upregulated markedly later than IL-18 activation, and Nlrp3(-/-) and Il18(-/-) mice did not show ISO-induced galectin-3 upregulation. It was further revealed that cardiomyocyte-derived IL-18 induced galectin-3 expression in macrophages following ISO treatment. Moreover, galectin-3 deficiency suppressed ISO-induced cardiac inflammation and fibrosis without blocking ISO-induced IL-18 increase. Treatment with a galectin-3 inhibitor, but not a beta-blocker, one day after ISO treatment effectively attenuated cardiac inflammation and injury. In conclusion, galectin-3 is upregulated to exaggerate cardiac inflammation and injury following acute beta-AR activation, a galectin-3 inhibitor effectively blocks cardiac injury one day after beta-AR insult.