The Biological Role of Klotho Protein in the Development of Cardiovascular Diseases

Abstract

Klotho is a membrane-bound or soluble antiaging protein, whose protective activity is essential for a proper function of many organs. In 1997, an accidental insertion of a transgene led to creation of transgenic mice with several age-related disorders. In Klotho-deficient mice, the inherited phenotypes closely resemble human aging, while in an animal model of Klotho overexpression, the lifespan is extended. Klotho protein is detected mainly in the kidneys and brain. It is a coreceptor for fibroblast growth factor and hence is involved in maintaining endocrine system homeostasis. Furthermore, an inhibition of insulin/insulin-like growth factor-1 signaling pathway by Klotho regulates oxidative stress and reduces cell death. The association between serum Klotho and the classic risk factors, as well as the clinical history of cardiovascular disease, was also shown. There are a lot of evidences that Klotho deficiency correlates with the occurrence and development of coronary artery disease, atherosclerosis, myocardial infarction, and left ventricular hypertrophy. Therefore, an involvement of Klotho in the signaling pathways and in regulation of a proper cell metabolism could be a crucial factor in the cardiac and vascular protection. It is also well established that Klotho protein enhances the antioxidative response via augmented production of superoxide dismutase and reduced generation of reactive oxygen species. Recent studies have proven an expression of Klotho in cardiomyocytes and its increased expression in stress-related heart injury. Thus, the antioxidative and antiapoptotic activity of Klotho could be considered as the novel protective factor in cardiovascular disease and heart injury.

Figures

Figure 1

The scheme of membrane-bound and soluble (shed and secreted) forms of αKlotho. (a) Membrane-bound αKlotho is created by 3 domains: cytoplasmic (CYT), transmembrane (TM), and ectodomain. The ectodomain has two internal repeats, KL1 and KL2. Membrane-bound αKlotho is subjected to shedding of ectodomain by ADAM 10 or 17 protease in two ways to release three shed αKlotho. The alternative transcriptional termination of kl gene expression leads to generation of secreted αKlotho. (b) Membrane-bound αKlotho forms a complex with FGFR to create a high-affinity binding site for FGF23. ADAM, a disintegrin and metalloproteinase domain-containing protein; FGFR, fibroblast growth factor receptor; FGF23, fibroblast growth factor 23.

Figure 2

The scheme of an expected mechanism by which Klotho protein is involved in cardiovascular diseases. (a) Local deficiency of vascular-derived Klotho leads to calcification. It is related to the FGFR/FGF23 resistance, which in turn inhibits the anticalcific effect of FGF23. An attenuated expression of Klotho protein in vessel wall reduces production of NO and increases formation of ROS. Therefore, an imbalance of Klotho and FGF23 leads to oxidative stress and endothelial dysfunction. (b) Depletion of Klotho can promote the prooxidative, proinflammatory, proapoptotic activity and damage of cardiomyocytes in the state of CVD risk. As a consequence, cardiac dysfunction and cardiomyopathy may be observed. (c) Klotho deficiency and KL gene polymorphisms are the risk factors for cardiovascular disease and correlate with the development of atherosclerosis, CAD, MI, or LVH. (d) An occurrence of cardiac hypertrophy and remodeling in the state of Klotho deficiency is related to oxidative stress. It is caused by the activation of p38 and ERK1/2 signaling pathways, as well as by the overexpression of TRPC6 channels in heart. The treatment with exogenous Klotho may provide protection against the fibrotic alterations. (e) Klotho contributes to alleviation of cardiac dysfunction and pathological changes in toxemic and ischemic heart. The treatment with Klotho mitigates an inflammation, ROS generation, apoptosis, mitochondrial dysfunction, fibrosis, and hypertrophy. Klotho may induce the restoration of cardiac function and thus could be explored as a therapeutic factor in myocardial injury. FGFR, fibroblast growth factor receptor; FGF23, fibroblast growth factor 23; NO, nitric oxide; ROS, reactive oxygen species; CAD, coronary artery disease; MI, myocardial infarction; LVH, left ventricular hypertrophy; ERK1/2, extracellular signal-regulated kinase 1/2; TRPC6, transient receptor potential canonical 6; , induction; , reduction.

Figure 3

Schematic representation of FGFR1/FGF21/βKlotho complex actions in the cardiomyocytes. (a) FGF21 is produced mainly in the liver and adipose tissue. (b) Different cardiac stress stimuli activate Sirt1-PPARα pathway in the heart. It leads to production of FGF21 in the cardiomyocytes in an autocrine manner. (c) FGF21 creates a complex with membrane-bound βKlotho and FGFR1 in the cardiac cells. Activation of FGFR1/FGF21/βKlotho network induces cardioprotection. (d) The activation of cell survival PI3K/Akt1 pathway leads to phosphorylation of BAD. It exerts the separation of antiapoptotic proteins Bcl-XL and Bcl-2 and inhibits the activity of caspase-3. As a result, the apoptosis of cardiac cells is reduced. (e) FGFR1/FGF21/βKlotho signaling regulates genes encoding proteins involved in antioxidant pathways: UCP3 and SOD2. It decreases ROS production and oxidative stress in cardiac cells. (f) The main intracellular pathway responsible for FGFR1/FGF21/βKlotho action is ERK. PGC1α is a transcriptional coactivator of PPARγ, involved in the control of energy metabolism and oxidative stress. The activation of PGC1α represses expression of proinflammatory cytokines by targeting NF-κB signaling. It also enhances energy supply by regulation of cardiac lipid metabolism. BAD, Bcl-2-associated death promoter; ER, endoplasmic reticulum; ERK, extracellular signal regulated kinase; FGF21, fibroblast growth factor 21; FGFR1, fibroblast growth factor receptor 1; NF-κB, nuclear factor-kappa-B; PGC1α, PPARγ co-activator-1 α; PI3K/Akt1, phosphatidylinositol 3-kinase/Akt serine/threonine kinase 1; PPARα, peroxisome proliferator-activated receptor-α; ROS, reactive oxygen species; Sirt1, Sirtuin 1; SOD2, superoxide dismutase 2; UCP3, uncoupling protein 3; +, upregulation/increase; -, downregulation/decrease.