TI - Discussion . AB - PGC-1alpha , an important transcriptional coactivator , plays a key role in energy metabolism [14] , [15] . PGC-1alpha expression is highly related to glucose metabolism , and its expression level changes in various tissues in rodent models of diabetes . It has previously been shown that both mRNA and protein levels of PGC-1alpha were significantly reduced in adipose tissue from insulin-resistant subjects [23] . Similarly , decreases in the mRNA levels of PGC-1alpha were found in skeletal muscle from type 2 diabetics [21] . In contrast , PGC-1alpha mRNA levels are elevated in the liver [17] , [20] , as well as in hearts of rodents in models of both type 1 and type 2 diabetes [22] . These changes in PGC-1alpha levels served as a causal factor or as a mediator of the corresponding pathophysiologic processes . In addition to alterations of the insulin/glucagon axis , the direct effect of chronic hyperglycemia may affect the expression level of PGC-1alpha . In our previous study , we were the first to report that high glucose directly inhibits PGC-1alpha expression in isolated rat islets [25] . Here , we show that PGC-1alpha mRNA expression is inhibited in blood vessel media in STZ-diabetic rats . Further experiments revealed that high glucose directly , and dose-dependently , inhibits PGC-1alpha mRNA expression in cultured rat VSMCs ( Fig 1 ) . These results indicate that high glucose decreases PGC-1alpha expression in VSMCs both in vivo and in vitro . However , the precise mechanism through which high glucose regulates PGC-1alpha expression in VSMC needs further study . A large body of work has established that chronic hyperglycemia promotes VSMC proliferation and migration and contributes to the progress of diabetic atherosclerosis [1] -[3] . Previous studies show that the PPAR family of proteins may be involved in the process [7] . TZD inhibits VSMC proliferation and migration through the activation of PPARgamma , which tends to inhibit the expression of several genes involved in ERK -dependent mitogenic response , leading to the inhibition of cell growth and , finally , cell migration [8] -[12] . Given that PGC-1alpha acts as a transcriptional coactivator for PPARgamma , thus regulating many physiological processes [13] -[15] , we hypothesized that the downregulation of PGC-1alpha by glucose may play a role in an in vitro model of VSMC proliferation and migration induced by hyperglycemia . Our results show that overexpression of PGC-1alpha by adenoviral infection abolishes ( Fig 2 ) , while suppression of PGC-1alpha amplifies ( Fig 3 ) hyperglycemia -induced VSMC proliferation and migration , providing evidence for a direct role of PGC-1alpha in this process . As the prevalent saturated FFA in circulation , palmitic acid has been shown to down-regulate PGC-1alpha expression in muscle cells [26] . Our previous study found that palmitic acid had no effect on VSMC proliferation and migration , but can markedly increase PGC-1alpha expression in VSMCs [24] . The mixtures of palmitic acid and high glucose exhibit no stimulatory effect on VSMC proliferation and migration accompanying a persisting induction of PGC-1alpha ( Fig 4 ) . When PGC-1alpha is knocked down by siRNA interference , the stimulatory effect of high glucose on VSMC proliferation and migration was restored even in presence of palmitic acid ( Fig 5 ) , indicating that PGC-1alpha is an integration point downstream of various nutrient -dependent signals that regulate VSMC proliferation and migration . It was previously shown that high glucose induces mitogenesis in VSMCs through increasing extracellular signal-regulated kinase ( ERK ) activity [3] -[6] . Activation of ERKs subsequently leads to the PHOSphorylation and the activation of a number of downstream targets , such as Elk-1 and Ets-1 , which evoke c-Fos and MMP-9 and contribute to VSMCs growth and migration , respectively . In the present study , high glucose markedly increased phosphorylaTED ERK1/2 protein levels in VSMCs , whereas overexpression of PGC-1alpha completely abolished this PHOSphorylation ( Fig 6 ) . However , little effect is observed either on VSMC proliferation and migration or on the activity of ERK1/2 when PGC-1alpha was overexpressed in the VSMCs without high glucose stimulation , indicating that the inhibitory effect of PGC-1alpha on VSMC proliferation and migration only exists in the cells which have been exposed and responded to the mitogenic signal , instead of quiescent VSMCs . These data suggest PGC-1alpha inhibits high glucose-induced ERK activity in VSMCs and negative regulation of PGC-1alpha in VSMC proliferation and migration is achieved by inhibiting nuclear ERK MAPK signaling . Our results confirmed to the previous report which showed that overexpression of PGC-1alpha abolished oleic/ acid induced ERK1/2 activity . However , it also reported that PGC-1alpha expression was regulated in skeletal muscle cells through a mechanism involving MAPK-ERK and NF-kappaB activation ( 26 ) , suggesting the interaction between PGC-1alpha expression and ERK1/2 PHOSphorylation are different in various cell types . The differences may attribute to different mechanism involved and may relate to the regulation of specific cell function . In VSMCs , given that PPARgamma has been reported to act as an inhibitory factor upstream of the ERK MAPK pathway ( 9-12 ) and PGC-1alpha is a co-activator of PPARgamma , the inhibitory effect of PGC-1alpha on ERK activity may be mediated through the coactivation of PPARgamma . The precise mechanisms of PGC-1alpha regulation on ERK activity merit further study . In summary , our results suggest that high glucose increases VSMC proliferation and migration through PGC-1alpha . Experimental elevation of PGC-1alpha ( by adenoviral overexpression or incubation with palmitic acid ) inhibits high glucose-induced VSMC proliferation and migration . Thus , our results reveal a novel function of PGC-1alpha as a regulator of VSMC proliferation and migration , and provide a potential strategy of treatment for diabetic atherosclerosis .