Implications of Klotho in vascular health and disease

Abstract

Cardiovascular disease (CVD) is a prevalent condition in general population and the first cause of death overall. Klotho, a pleiotropic protein related to longevity that acts as a co-receptor of the fibroblast growth factor 23, has been proposed as a key regulator of the development of CVD. In the few clinical studies made, it has been observed a relationship between low levels of soluble Klotho and the occurrence and severity of CVD, as well as a reduction of cardiovascular risk when they are high. Also, different polymorphisms of human Klotho gene have been related to the incidence of cardiovascular events. Moreover, several experimental studies indicate that this protein acts in the maintenance of vascular homeostasis. Klotho improves endothelial dysfunction through promotion of NO production and mediates anti-inflammatory and anti-aging effects such as suppression of adhesion molecules expression, attenuation of nuclear factor-kappa B or inhibition of Wnt signaling. Furthermore, this protein is related to the attenuation of vascular calcification as well as prevention of cardiac hypertrophy. The expression of this protein in the vascular wall implies a new scenario for the treatment of vascular disorders. The purpose of this review is to provide an overview of the relationship between the Klotho protein and CVD, in addition to its role in the maintenance of functional vascular integrity.

Relationship of Serum Soluble Klotho Levels and Echocardiographic Parameters in Patients on Maintenance Hemodialysis

“…Klotho protein can inhibit insulin/insulin-like growth factor (IGF1) signaling and in this way promote resistance to oxidative stress [18]. In cultured HUVECs, incubation with Klotho results in suppression of expression of cell adhesion molecules, attenuates the activation of NF-κB, and blocks tumor necrosis factor-α-induced monocyte adhesion [35, 36]. Klotho deficiency might be involved in microinflammatory state in MHD patients, and the correlation of hs-CRP and IVST may be partly attributed to Klotho deficiency.…”

Nicotinamide Riboside Delivery Generates Nad+ Reserves to Protect Vascular Cells Against Oxidative Damage

“…The Klotho gene codes for a membrane protein that is associated with β-glucosidase and defects have been linked to chronic renal failure as well as ageing. More recent evidence has supported Klotho gene's role in inhibiting ROS production and attenuating inflammation (29,30). Thus, interventions to improve vascular function in aged organisms may hinge on managing cellular ROS production and/or the subsequent oxidative stress response.…”

Deficiency of the anti-ageing hormone Klotho as a potential predictor of coronary artery disease

“…A defect in Klotho gene expression in the mouse result in a phenotype similar to premature human aging, including endothelial dysfunction, progressive atherosclerosis, and shortened lifespan [2,3]. Soluble Klotho, a proteolytic cleavage of the extracellular domain of Klotho, is detectable in the blood, urine, and cerebrospinal fluid [4]. Soluble Klotho has been implicated in anti-apoptotic effects on vascular endothelial cells and cardiovascular protective properties [5,6].…”