Copyright © 2005, European Society of Cardiology
Soluble guanylate cyclase (sGC) down-regulation by abnormal extracellular matrix proteins as a novel mechanism in vascular dysfunction: Implications in metabolic syndrome
Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
* Tel.: +1 317 274 9765; fax: +1 317 274 3318. Email address: spacker1{at}iupui.edu
Received 23 November 2005; accepted 7 December 2005
Vascular dysfunction plays a role in most if not all cardiovascular disorders. Vascular dysfunction is defined as impaired vasodilation in response to agonists such as acetylcholine (ACh) that mediate vascular smooth muscle relaxation through release of the endothelial derived relaxing factor (EDRF) nitric oxide (NO). There is a wealth of literature to support the understanding that endothelial dysfunction is due to a decreased NO synthesis or an increased NO inactivation. Endothelial dysfunction is generally thought to be responsible for vascular dysfunction, and the terms are often used interchangeably. But the mechanism(s) responsible for vascular dysfunction is (are) far from being completely understood, and labeling all vascular dysfunction as endothelial dysfunction may be application of a misnomer in some cases. Alterations in the cell signaling cascade downstream of NO production and release could explain vascular dysfunction in certain conditions. Nowadays, it is textbook information that NO induces cell relaxation by interacting with sGC and causing an increase in cyclic guanosine monophosphate (cGMP). The end result is thought to be a decrease in intracellular cytoplasmic calcium due to decreased intracellular calcium release [1] and/or increased cGMP-dependent calcium pump activity [1] and/or due to decreased calcium influx because of the opening of K+ channels, resulting in hyperpolarization and the consequent closing of L-type Ca2+ channels [1,2]. So, could vascular dysfunction be explained by alterations in the target tissue response to NO? In particular, could alterations in smooth muscle sGC or cGMP or vasodilator-stimulated phosphoprotein (VASP) or K+ and Ca2+ channel function be responsible for vascular dysfunction even when endothelial NO release is normal or high? If so, what might cause alterations in vascular smooth muscle sGC, cGMP, VASP, or the relevant ion channel proteins?
The Rodriguez–Puyol laboratory has previously shown that endothelial dysfunction (i.e. decreased endothelial NO synthesis) could be the consequence of the accumulation of abnormal extracellular matrix (ECM) proteins in vascular walls [3]. In the current issue of the Journal, Diéz-Marqués et al. present data that show that exogenous modification of ECM proteins can alter vascular smooth muscle sGC content or alter the response of sGC to NO stimulation [4]. Specifically, these investigators show that incubation of human mesangial cells and aortic smooth muscle cells with arginine-glycine-aspartic acid (RGD)-containing polypeptide caused an increase in sGC content. As pointed out by the authors, RGD motifs are present in various ECM proteins and are known to interact with certain integrins. Furthermore, Diéz-Marqués et al. report that arginine-glycine-aspartate-serine (RGDS) preincubation enhanced the sodium nitroprusside (SNP) relaxation response of H2O2- and angiotensin II (AII)-contracted human mesangial and aortic smooth muscle cells, respectively. These studies suggest that altered ECM proteins causing down-regulation of sGC could be a mechanism to explain vascular dysfunction. This novel mechanism would have particular relevance to cardiovascular disorders associated with metabolic syndrome in which vascular wall proteins are subject to change due to the high glycosylating and oxidizing environment. Results presented in the paper by Diéz-Marqués et al. also suggest that exogenous modification of ECM proteins can result in reversal of sGC down-regulation. Studies of contractility and relaxation behavior in isolated vessels from appropriate animal models will determine if RGD treatment reverses not only sGC down-regulation but also the consequent vascular dysfunction. The Diéz-Marqués et al. findings may provide the basis of new knowledge that will significantly impact the development of novel therapeutic agents for the management of disorders such as non-insulin-dependent diabetes mellitus (NIDDM)-associated hypertension.
An intriguing additional result has come out of the work by Diéz-Marqués et al. that has to do with the fact that two very different agonists, H2O2 and AII, were used to contract the mesangial and aortic muscle cells in experiments investigating the relaxation response to SNP [4]. There is generally agreement that myosin light chain phosphorylation is the final step in the AII receptor-activated signal transduction pathway resulting in contraction of smooth muscle [5,6]. Whether AII requires calcium as a second messenger in mediating contraction is somewhat controversial [6]. In contrast, H2O2 causes contraction by a regulatory signaling mechanism that is alternate to the calcium-calmodulin-MLCK-MLC-phosphorylation cascade known to be the primary signal transduction pathway in smooth muscle contraction in response to most other physiological agonists. Hydrogen peroxide mediates calcium-independent and myosin phosphorylation-independent smooth muscle contraction [7]. If the same signaling mechanism is employed in H2O2-induced mesangial cell contraction as is utilized in H2O2-induced smooth muscle contraction, then a decreased intracellular cytoplasmic Ca2+ concentration cannot be the final step in the mechanism by which SNP or NO or sGC mediate relaxation. So, how does SNP or sGC mediate relaxation of H2O2-stimulated contractions? Would VASP, sGC, and cGMP be involved in this particular atypical case? Diéz-Marqués et al. may have serendipitously produced results that challenge the existing paradigm of the current state-of-the-art understanding of the mechanism of NO/sGC-mediated smooth muscle relaxation.
Vascular production of reactive oxygen species can increase substantially [8] in disease states such as hypertension [9], coronary artery disease [10], and atherosclerosis [11]. H2O2 levels within the concentration range that has been shown to cause contraction in isolated vascular muscle [7] have been detected in people under both physiological and pathophysiological conditions [12–14]. Thus, it is possible that oxidant stimulation of vascular muscle could play a role in hypertension. Dyslipidemia is also associated with diabetes. The fact that low density lipoprotein (LDL) cholesterol levels are elevated in diabetic patients is also of relevance. Oxidized LDL has been shown to be a direct vasoconstrictor [15]. Therefore, high LDL levels in the higher than normal oxidizing environment that occurs in diabetes would suggest excessive oxidized LDL levels in these patients. Elevated circulating levels of vasoactive oxidants could cause increased vasoconstriction and, consequently, the hypertension associated with diabetes. Elucidation of the signaling pathway of vasoconstrictor oxidants such as H2O2 and oxidized LDL and of the cellular mechanism by which activation of sGC mediates relaxation of oxidant-induced contraction may prove to be of paramount importance in this era of a metabolic syndrome epidemic.
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Acknowledgement |
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The author is grateful to Dr. GM Dick for his insightful suggestions regarding the potential role of potassium channels.
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Notes |
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* See article by Diéz-Marqués et al. [4] (pp. 359–369) in this issue.
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