Soluable α-klotho Reduces Cardiac Fibrosis in Mice
Klotho is a longevity-related gene. In mice, greater expression extends life while reduced expression shortens life. Most study has focused on beneficial effects on cognition and kidney function, with some debate over where in the body it acts - it may be that benefits to brain function are entirely the consequence of improved kidney function. That isn't all that klotho does, however. The delivery of soluble α-klotho has emerged as a basis for building therapies based on klotho biochemistry, and Unity Biotechnologies is one of the groups working on clinical development of this line of work. Here, researchers show that the scarring of fibrosis in heart tissue, a feature of aging, can be reduced via delivery of α-klotho. The same questions apply here as for the brain; is this a local mechanism of action, or something mediated by effects in another organ and systemic signaling throughout the body?
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.
FGF23 is the most recently discovered fibroblast growth factor and functions as an endocrine hormone that regulates phosphate homeostasis through binding to FGFR and KL, its coreceptor in the kidney and parathyroid glands. Elevated levels of circulating FGF23 have been associated with left ventricular hypertrophy, and it has been suggested that FGF23 exerts a direct effect on the myocardium. Interestingly, the co-receptor of FGF23, KL, has been shown to exhibit renal protective functions independent of FGF23/FGFR signaling.
We found that the anti-apoptotic function of soluble KL in isoproterenol-treated 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.
Hope it can be used to reduce scars inside heart after heart surgery. even children have died of blood cloths resulting from it.
I wonder if it could reduce fibrosis of lymph nodes if directly injected into them? This could assist therapies aimed at thymus regeneration such as Repair Biotechnologies FOXN1 gene therapy.