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Soluble Alpha-Klotho Alleviates Cardiac Fibrosis without Altering Cardiomyocytes Renewal
1Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City 83301, Taiwan.
Insights
The anti-aging protein alpha-klotho (KL) protects the heart by reducing cell death and promoting survival in heart muscle and blood vessel cells, offering potential as a therapeutic agent for heart disease.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Aging Research
Background:
- Heart disease remains the leading global cause of mortality.
- Myocardial infarction and subsequent cardiac remodeling lead to heart failure.
- The role of the anti-aging protein alpha-klotho (KL) in cardiac repair is largely unexplored.
Purpose of the Study:
- To investigate the function of alpha-klotho (KL) in cardiac regeneration, fibrosis, and repair.
- To determine if KL's cardioprotective effects are mediated by fibroblast growth factor-23 (FGF23).
Main Methods:
- In vitro studies using isoproterenol-treated H9c2 cardiomyocytes.
- In vivo studies involving isoproterenol-induced cardiac injury in mice.
- Genetic fate-mapping models to assess cardiomyocyte proliferation.
Main Results:
- Soluble KL exhibited anti-apoptotic effects on cardiomyocytes independent of FGF23 in vitro.
- KL treatment reduced cardiac fibrosis, cardiomyocyte apoptosis, and endothelial cell apoptosis in vivo.
- KL treatment increased microvessel density and endothelial cell proliferation in injured myocardium.
- No significant cardiomyocyte proliferation was observed with or without KL treatment.
Conclusions:
- Alpha-klotho (KL) confers cardioprotection primarily through anti-apoptotic and pro-survival mechanisms in cardiomyocytes and endothelial cells.
- KL's therapeutic potential lies in its ability to mitigate cardiac injury and promote vascular repair.
- KL represents a promising candidate for developing novel cardioprotective therapies.
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.
