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

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.