Redox regulation of cGMP-dependent protein kinase Iα in the cardiovascular system

Abstract

Elevated levels of oxidants in biological systems have been historically referred to as “oxidative stress,” a choice of words that perhaps conveys an imbalanced view of reactive oxygen species in cells and tissues. The term stress suggests a harmful role, whereas a contemporary view is that oxidants are also crucial for the maintenance of homeostasis or adaptive signaling that can actually limit injury. This regulatory role for oxidants is achieved in part by them inducing oxidative post-translational modifications of proteins which may alter their function or interactions. Such mechanisms allow changes in cell oxidant levels to be coupled to regulated alterations in enzymatic function (i.e., signal transduction), which enables “redox signaling.” In this review we focus on the role of cGMP-dependent protein kinase (PKG) Ia disulfide dimerisation, an oxidative modification that is induced by oxidants that directly activates the enzyme, discussing how this impacts on the cardiovascular system. Additionally, how this oxidative activation of PKG may coordinate with or differ from classical activation of this kinase by cGMP is also considered.

Relaxing Responses to Hydrogen Peroxide and Nitric Oxide in Human Pericardial Resistance Arteries Stimulated with Endothelin‐1

“…The observed comparable relaxing potencies of exogenous H 2 O 2 in arteries contracted by K + , U46619 or ET-1 in the presence of inhibitors of mechanisms of EDR go against the second part of our hypothesis; namely, that ET-1 would promote the H 2 O 2 /PKG/BK Ca pathway in ASMC as observed with oxidative stress [14,32,34,35].…”

“…They rapidly scavenge NO and inhibit its stimulatory effects on sGC [15,32]. Hereby, ASMC levels of cGMP are reduced and activity of cGMP-dependent PKGIa is reduced, while levels of oxidized cGMP-independent dimers of PKGIa, which can be stimulated by H 2 O 2 and activate BK Ca , are increased [4,14,33,34]. Despite these candidate mechanisms, (i) the relaxing potency of the NO donor compound SNP did not differ between arteries stimulated with K + , U46619 or ET-1 and (ii) the relaxing potency of exogenously administered H 2 O 2 did not differ between contractions stimulated by either of the three contractile stimuli in the presence of several inhibitors of EDR.…”

Oxidant sensor in the cGMP-binding pocket of PKGIα regulates nitroxyl-mediated kinase activity

“…However, oxidation of Cys42 may not induce substantive catalytic activation compared to cGMP-dependent activation of the kinase 25 . Given that Cys42 is localised in the N-terminal leucine zipper domain that is important for substrate targeting 26 , the redox state of this thiol may be more important for modulating such interactions, as suggested previously 27 – 29 . Consistent with this regulatory role, Cys42Ser PKGIα knock-in (KI) mice, which cannot form the interprotein disulfide, are hypertensive 30 , illustrating a physiological role for oxidants in blood pressure regulation.…”

The Emerging Roles of Nicotinamide Adenine Dinucleotide Phosphate Oxidase 2 in Skeletal Muscle Redox Signaling and Metabolism

“…Examples in mammals of these cellular processes include growth factor signaling, hypoxic signal transduction, autophagy, immune responses, cell proliferation, and differentiation or metabolic reprogramming, to name a few. It is not the purpose of this section to provide a comprehensive list of different types of mammalian redoxregulated proteins, but, instead, we suggest recent reviews that provide examples of redox-regulated kinases, phosphatases, and transcription factors involved in cancer and cell proliferation (121), hypoxia (327), inflammatory processes (219), blood pressure homeostasis (289), and glycemic control (273), among others.…”