Regulation of NAD(P)H oxidases by AMPK in cardiovascular systems

Abstract

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are ubiquitously produced in cardiovascular systems. Under physiological conditions, ROS/RNS function as signaling molecules that are essential in maintaining cardiovascular function. Aberrant concentrations of ROS/RNS have been demonstrated in cardiovascular diseases owing to increased production or decreased scavenging, which have been considered common pathways for the initiation and progression of cardiovascular diseases such as atherosclerosis, hypertension, (re)stenosis, and congestive heart failure. NAD(P)H oxidases are primary sources of ROS and can be induced or activated by all known cardiovascular risk factors. Stresses, hormones, vasoactive agents, and cytokines via different signaling cascades control the expression and activity of these enzymes and of their regulatory subunits. But the molecular mechanisms by which NAD(P)H oxidase is regulated in cardiovascular systems remain poorly characterized. Investigations by us and others suggest that adenosine monophosphate-activated protein kinase (AMPK), as an energy sensor and modulator, is highly sensitive to ROS/RNS. We have also obtained convincing evidence that AMPK is a physiological suppressor of NAD(P)H oxidase in multiple cardiovascular cell systems. In this review, we summarize our current understanding of how AMPK functions as a physiological repressor of NAD(P)H oxidase.

Fig. 1

Distribution and regulation of NAD(P)H oxidases in cardiovascular systems. With the exception of Nox4, the Nox homologues are basally inactive. Regulation of the cardiovascular Nox complex is mediated by variations of Nox isoform structure as well as interactions with various partners. See text for details.

Fig. 2

Structure features of the catalytic α and regulatory β and γ subunits of AMPK. Residues phosphorylated by AMPKK (LKB1, CaMKKβ, TAK1), PKA, and Akt are shown within the α subunit. This figure is modified from Viollet et al [149]. Refer to the text for expanded forms of abbreviations.

Fig. 3

Schematic summary of available information on the regulation of cardiovascular Nox by AMPK. Refer to the text for expanded forms of abbreviations.