Structures of soluble guanylate cyclase: implications for regulatory mechanisms and drug development

Activation of cGMP synthesis leads to vasodilation, and is an important mechanism in clinical treatment of angina, heart failure, and severe peripheral and pulmonary hypertension. The nitric oxide-responsive sGC (soluble guanylate cyclase) has been the target of recent drug discovery efforts. The present review surveys recent data on the structure and regulation of sGC, and the prospects of new avenues for therapeutic intervention.

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Soluble guanylate cyclase stimulator attenuates acute pulmonary hypertension and augments the pulmonary vasodilator response to inhaled nitric oxide in awake lambs

BMC Pharmacology ◽

10.1186/1471-2210-5-s1-s28 ◽

2005 ◽

Vol 5 (Suppl 1) ◽

pp. S28

Author(s):

Oleg V Evgenov ◽

Fumito Ichinose ◽

Natalia V Evgenov ◽

Mark J Gnoth ◽

Kenneth D Bloch ◽

...

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Guanylate Cyclase ◽

Soluble Guanylate Cyclase ◽

Inhaled Nitric Oxide ◽

Vasodilator Response ◽

Pulmonary Vasodilator ◽

Soluble Guanylate Cyclase Stimulator ◽

Acute Pulmonary Hypertension

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Regulation of the endogenous NO pathway by prolonged inhaled NO in rats

Journal of Applied Physiology ◽

10.1152/jappl.1998.85.3.1070 ◽

1998 ◽

Vol 85 (3) ◽

pp. 1070-1078 ◽

Cited By ~ 24

Author(s):

Deborah U. Frank ◽

Damian J. Horstman ◽

Geoffrey N. Morris ◽

Roger A. Johns ◽

George F. Rich

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Guanylate Cyclase ◽

Soluble Guanylate Cyclase ◽

Protein Levels ◽

Cgmp Pathway ◽

Isolated Lungs ◽

Oxide Synthase ◽

Inhaled No ◽

Enos Protein

Nitric oxide (NO) modulates the endogenous NO-cGMP pathway. We determined whether prolonged inhaled NO downregulates the NO-cGMP pathway, which may explain clinically observed rebound pulmonary hypertension. Rats were placed in a normoxic (N; 21% O2) or hypoxic (H; 10% O2) environment with and without inhaled NO (20 parts/million) for 1 or 3 wk. Subsequently, nitric oxide synthase (NOS) and soluble guanylate cyclase (GC) activity and endothelial NOS (eNOS) protein levels were measured. Perfusate cGMP levels and endothelium-dependent and -independent vasodilation were determined in isolated lungs. eNOS protein levels and NOS activity were not altered by inhaled NO in N or H rats. GC activity was decreased by 60 ± 10 and 55 ± 11% in N and H rats, respectively, after 1 wk of inhaled NO but was not affected after 3 wk. Inhaled NO had no effect on perfusate cGMP in N lungs. Inhaled NO attenuated the increase in cGMP levels caused by 3 wk of H by 57 ± 11%, but there was no rebound in cGMP after 24 h of recovery. Endothelium-dependent vasodilation was not altered, and endothelium-independent vasodilation was not altered (N) or slightly increased (H, 10 ± 3%) by prolonged inhaled NO. In conclusion, inhaled NO did not alter the endogenous NO-cGMP pathway as determined by eNOS protein levels, NOS activity, or endothelium-dependent vasodilation under N and H conditions. GC activity was decreased after 1 wk; however, GC activity was not altered by 3 wk of inhaled NO and endothelium-independent vasodilation was not decreased.

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Soluble guanylate cyclase gene expression and localization in rat lung after exposure to hypoxia

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1999.277.4.l841 ◽

1999 ◽

Vol 277 (4) ◽

pp. L841-L847 ◽

Cited By ~ 28

Author(s):

Dechun Li ◽

Nan Zhou ◽

Roger A. Johns

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Enzyme Activity ◽

Smooth Muscle ◽

Guanylate Cyclase ◽

Soluble Guanylate Cyclase ◽

Muscle Tone ◽

Rat Lung ◽

Sprague Dawley ◽

Rat Lungs

The nitric oxide (NO)-cGMP signal transduction pathway plays an important role in the regulation of pulmonary vascular tone and resistance in pulmonary hypertension. A number of studies have demonstrated that endothelial (e) and inducible nitric oxide synthases (NOS) are upregulated in hypoxia-exposed rat lung. These changes in NOS expression have been found to correlate with the process of pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension, and remodeling is increased in the absence of eNOS. In this study, we examined the expression and localization of soluble guanylate cyclase (sGC), the primary receptor for NO, in hypoxia- and normoxia-treated rat lungs. Male Sprague-Dawley rats were exposed to hypoxia (10% O2, normobaric) or normoxia for 1, 3, 5, and 21 days. The lungs were used for Western analysis of sGC protein, sGC enzyme activity, immunohistochemistry using antiserum against sGC α1- and β1-subunits, and nonradioactive in situ hybridization (NRISH) using a digoxigenin-labeled sGC α1-subunit cRNA probe. Western blot analysis revealed a more than twofold increase of sGC protein α1-subunit in rat lungs exposed to 3, 5, and 21 days of hypoxia, correlating well with sGC enzyme activity. Immunohistochemistry and NRISH demonstrated increased expression of sGC in the smooth muscle cells of the pulmonary arteries and arterioles in the hypoxic rat lungs when compared with normoxic controls. Based on our results, the upregulation of sGC may play an important role in the regulation of smooth muscle tone and pressure in the pulmonary circulation during chronic hypoxia.

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Soluble guanylate cyclase in NO signaling transduction

Reviews in Inorganic Chemistry ◽

10.1515/revic-2013-0011 ◽

2013 ◽

Vol 33 (4) ◽

pp. 193-205

Author(s):

Jie Pan ◽

Fangfang Zhong ◽

Xiangshi Tan

Keyword(s):

Nitric Oxide ◽

Heart Failure ◽

Guanylate Cyclase ◽

Soluble Guanylate Cyclase ◽

Signaling Transduction ◽

Function Mechanism ◽

The Past ◽

No Signaling ◽

Sgc Activators ◽

Sgc Stimulators

AbstractNitric oxide (NO), a signaling molecule in the cardiovascular system, has been receiving increasing attention since Furchgott, Ignarro, and Murad were awarded the Nobel Prize in Physiology and Medicine for the discovery in 1998. Soluble guanylate cyclase (sGC), as an NO receptor, is a key metalloprotein in mediating NO signaling transduction. sGC is activated by NO to catalyze the conversion of guanosine 5′-triphosphate (GTP) to cyclic guanylate monophosphate (cGMP). The dysfunction of NO signaling results in many pathological disorders, including several cardiovascular diseases, such as arterial hypertension, pulmonary hypertension, heart failure and so on. Significant advances in its structure, function, mechanism, and physiological and pathological roles have been made throughout the past 15 years. We herein review the progress of sGC on structural, functional investigations, as well as the proposed activation/deactivation mechanism. The heme-dependent sGC stimulators and heme-independent sGC activators have also been summarized briefly.

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