AMPK, metabolism, and vascular function

Abstract

Adenosine monophosphate‐activated protein kinase (AMPK) is a cellular energy sensor activated during energy stress that plays a key role in maintaining energy homeostasis. This ubiquitous signaling pathway has been implicated in multiple functions including mitochondrial biogenesis, redox regulation, cell growth and proliferation, cell autophagy and inflammation. The protective role of AMPK in cardiovascular function and the involvement of dysfunctional AMPK in the pathogenesis of cardiovascular disease have been highlighted in recent years. In this review, we summarize and discuss the role of AMPK in the regulation of blood flow in response to metabolic demand and the basis of the AMPK physiological anticontractile, antioxidant, anti‐inflammatory, and antiatherogenic actions in the vascular system. Investigations by others and us have demonstrated the key role of vascular AMPK in the regulation of endothelial function, redox homeostasis, and inflammation, in addition to its protective role in the hypoxia and ischemia/reperfusion injury. The pathophysiological implications of AMPK involvement in vascular function with regard to the vascular complications of metabolic disease and the therapeutic potential of AMPK activators are also discussed.

Activation of AMP kinase ameliorates kidney vascular dysfunction, oxidative stress and inflammation in rodent models of obesity

“…Therefore, our findings demonstrate that endothelial dysfunction due to impaired PI3K/Akt/eNOS pathway is associated with defective AMPK-vasodilation in preglomerular arteries of genetically obese rats, as earlier reported for large conductance arteries (such as aorta) from diet-induced models of obesity (García-Prieto, Hernández-Nuño, et al, 2015). In contrast to the blunted endothelial (Rodríguez et al, 2020(Rodríguez et al, , 2021 Acute ex vivo treatment of whole arteries with A769662 augmented ACC phosphorylation and markedly enhanced eNOS activity and expression in LZR, thus supporting the involvement of the endothelial PI3K/Akt/NO pathway in AMPK-mediated renal vasodilation (Levine et al, 2007). In preglomerular arteries of obese rats, A769662 restored impaired endothelium-dependent relaxations by enhancing NOS expression.…”

“…AMPK activation is also involved in the EDH-mediated relaxations of resistance arteries, because this EDH type vasodilation is lost after specific knockout of the endothelial AMPKα1 subunit (Enkhjargal et al, 2014). Therefore, stimulation of endothelial IK Ca channels and of the EDH-type response, as recently reported in intrarenal arteries (Rodríguez et al, 2020(Rodríguez et al, , 2021, could also contribute to the A769662-induced restoration of endotheliumdependent relaxations in intrarenal arteries from obese rats. The beneficial effects of AMPK activation on renal endothelial dysfunction in the obese kidney were further assessed by in vivo administration of A769662 in the ob/ob model of genetic obesity/metabolic syndrome.…”

“…Accordingly, both isoprenaline and AMPK-mediated relaxations were unchanged by endothelial cell removal and resistant to NOS or PI3K blockade in kidney preglomerular arteries of obese rats thus confirming an impaired endothelial PI3K/NOS/NO pathway. Endothelium-mediated AMPK relaxations in renal arteries do not only involve NO but also an endothelium-derived hyperpolarization (EDH)-type component mediated by stimulation of IK Ca channels in endothelial cells (Rodríguez et al, 2020(Rodríguez et al, , 2021. However, it is unlikely that this non-NO, non-prostanoid, EDH component accounts for the defective AMPKmediated relaxations, because it is augmented to compensate for endothelial NO impairment in renal arteries in obesity (Muñoz et al, 2020).…”

“…Accordingly, the overall NADPH-dependent superoxide production was confirmed to be greatly augmented in preglomerular arteries of obese rats as earlier reported (Muñoz et al, 2015(Muñoz et al, , 2018, and both ex vivo and in vivo activation of AMPK were found to reduce vascular oxidative stress. AMPK reduces Nox4 expression in podocytes (Sharma et al, 2008) and modulates redox balance in kidney preglomerular arteries through both down-regulation of Nox4 expression and through inhibition of Nox2 activation (Rodríguez et al, 2020(Rodríguez et al, , 2021. The powerful suppression of superoxide production induced by ex vivo treatment with the AMPK activator A769662 in whole renal preglomerular arteries of OZR could mainly be ascribed to inhibition of Nox2, that generates superoxide, rather than down-regulation of Nox4.…”

Diabetes Mellitus and Cardiovascular Diseases: Nutraceutical Interventions Related to Caloric Restriction

“…Interestingly, AMPK and SIRT1 synergically act: Liver Kinase B1, a crucial upstream AMPK activator, is a main SIRT1 target [45]. Moreover, AMPK and SIRT1 have many common molecular targets involved in oxidative and inflammatory processes characterizing cardiometabolic pathologies, i.e., endothelial nitric oxide (NO) bioavailability, PCG-1α, and PPARs [38][39][40][41][42]46,47] (Figure 2). T2DM and CVD: AMPK-SIRT1 signaling cascade.…”