*6.2. Aggravation of Atherosclerosis by TCTP-Induced Survival of Macrophages in TCTP+/*<sup>−</sup> *Mice*

Pinkaew et al. described the pathophysiological roles of TCTP in protecting macrophages in atherosclerosis using heterozygous TCTP-deficient mice [45]. This group noted that TCTP, not hypertension per se, can facilitate atherosclerosis by protecting macrophages against apoptosis. They constructed mouse models of TCTP-deficient (TCTP+/−) and wild-type (TCTP+/+) mice on a hypercholesterolemic genetic background, Ldlr−/<sup>−</sup> Apobec1−/<sup>−</sup> whose low-density lipoprotein receptor (*Ldlr*) and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (*Apobec 1*) genes are lacking. Ldlr−/<sup>−</sup> Apobec1−/<sup>−</sup> mice have considerably elevated blood cholesterol levels on a normal diet and induce atherogenic processes from fatty streaks through the fibrous cap [45]. Of note, this group tried to find the role of TCTP itself by ruling out the effect of BP as there were no significant differences in BP between TCTP+/<sup>−</sup> and TCTP+/+ [45].

On a normal diet for 10 months, both groups of mice showed comparable BP and lipid profiles, but TCTP+/<sup>−</sup> had significantly less atherosclerosis in aortas compared to TCTP+/+ littermate controls [45], indicating that TCTP deficiency is related to a lesser degree of atherosclerosis. It was found that TCTP+/<sup>−</sup> mice had fewer macrophages within atherosclerotic plaques and more apoptotic macrophages in the intima than those of TCTP+/+ mice [45]. Moreover, peritoneal macrophages isolated from TCTP+/<sup>−</sup> mice showed elevated expression of Bax as well as apoptosis in the plaques both at baseline and upon oxidized LDL stimuli [45]. TCTP expression in peritoneal macrophages was more enhanced in hypercholesterolemic sera from Ldlr−/<sup>−</sup> Apobec1−/<sup>−</sup> mice than that from control mice. Additionally, macrophage colony-stimulating factor (M-CSF), which is elevated in the plasma of patients with coronary artery disease [98], induced TCTP expression [45]. Based on these findings, they concluded that the pro-atherosclerotic microenvironment, including hypercholesterolemia and inflammatory cytokines like M-CSF, allows the induction of TCTP expression in macrophages and this protects macrophages against Bax-induced apoptosis, thereby facilitating the propagation of macrophages and atherosclerosis [45]. Moreover, TCTP levels are abundantly elevated in human atherosclerotic plaques, showing a positive correlation with the severity of lesions from the fatty streak to the fibrous plaques [45].

A recent study using patients' data concluded that elevated TCTP in atherosclerotic lesions might result from the adaptive responses to profound apoptosis [99]. Higher plasma TCTP levels were found in the patients with coronary artery disease (CAD), particularly those with three-vessel disease (3VD) [99]. Furthermore, the degree of TCTP levels is positively correlated with the severity of CAD, suggesting it as a biomarker for CAD [99]. It was speculated that insufficient clearance of extensive apoptotic cells in atherosclerotic lesions might cause the accumulation of apoptotic cells and inflammatory responses that in turn induce the adaptive responses involving TCTP expression to reduce the excessive apoptosis [99].

Several lines of evidence unequivocally show the facilitative role of TCTP overexpression in atherosclerotic plaque formation via TCTP-induced hypertension or by reducing apoptosis in macrophages [44,45]. In this review, TCTP serves as a novel target for the modulation of hypertension-related atherosclerosis.

#### **7. Role of TCTP in Hypertension-Related Diseases**

Studies using genetically altered animal models, including conventional or tissuespecific TCTP-overexpressing and TCTP-deficient mice, have shed light on TCTP's potential pathophysiological role in chronic diseases, such as osteoporosis [42], rheumatoid arthritis [43], and allergy [46]. Other studies have indicated the protective roles of TCTP due to its anti-apoptotic and cell-protective functions. Such beneficial effects were found in the studies regarding diabetes [48], heart failure [49,50], and liver damage [51,52]. Additionally, TCTP promotes the energy expenditure and metabolic homeostasis that might be preventive of obesity-related metabolic disorders [47] (Table 1). Here, we briefly discuss the protective roles of TCTP in some conditions, including obesity and heart failure, among others, to help understand the plethora of TCTP functions in cardiovascular and metabolic diseases in vivo.
