Abstract
Heart disease is the leading cause of death worldwide. The major cause of heart failure is the death of the myocardium caused by myocardial infarction, detrimental cardiac remodeling, and cardiac fibrosis occurring after the injury. This study aimed at discovering the role of the anti-aging protein α-klotho (KL), which is the co-receptor of fibroblast growth factor-23 (FGF23), in cardiac regeneration, fibrosis, and repair. We found that the anti-apoptotic function of soluble KL in isoproterenol-treated H9c2 cardiomyocytes was independent of FGF23 in vitro. In vivo, isoproterenol-induced cardiac fibrosis and cardiomyocyte and endothelial cell apoptosis were reduced by KL treatment. Moreover, the number of Ki67-positive endothelial cells and microvessel density within the isoproterenol-injured myocardium were increased upon KL treatment. However, by using genetic fate-mapping models, no evident cardiomyocyte proliferation within the injured myocardium was detected with or without KL treatment. Collectively, the cardioprotective functions of KL could be predominantly attributed to its anti-apoptotic and pro-survival activities on endothelial cells and cardiomyocytes. KL could be a potential cardioprotective therapeutic agent with anti-apoptotic and pro-survival activities on cardiomyocytes and endothelial cells.
Highlights
Congestive heart failure is a leading cause of morbidity and mortality worldwide
Our results suggested that KL was cardioprotective, but its beneficial effects might not be attributed to the promotion of cardiomyocyte proliferation and cardiac regeneration in vivo
In a mouse model of uremic cardiomyopathy, exogenous administration of soluble KL exerts a beneficial effect independent of fibroblast growth factor-23 (FGF23) and phosphate [35]. These observations suggest that exogenous administration of soluble KL could be a potential treatment against cardiac fibrosis and that unidentified molecular mechanisms underlie its cardioprotective roles
Summary
Congestive heart failure is a leading cause of morbidity and mortality worldwide. There are an estimated 4.9 million cases of heart failure in the United States alone. The major non-surgical treatments for heart failure include administration of beta-blockers, angiotensin-converting-enzyme (ACE) inhibitors, aldosterone antagonists, and symptomatic treatment. These treatments are inadequate, and heart failure remains a progressive and often lethal disease in the majority of cases. Whereas the heart of some vertebrates like zebrafish and newts can undergo significant regeneration after injury, the myocardial regenerative response in adult mammals is dramatically reduced [2,3]. Recent studies demonstrate that humans can generate new heart cells [4], regeneration in the adult human heart is grossly inadequate to compensate for the severe loss of cardiomyocytes following myocardial infarction. Understanding how to guide heart cell regeneration is a critical goal
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