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

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.