The Soluble Guanylate Cyclase Stimulator BAY 41-2272 Inhibits Vascular Smooth Muscle Growth through the cAMP-Dependent Protein Kinase and cGMP-Dependent Protein Kinase Pathways

Joshi, Chintamani N; Martin, Danielle N; Fox, Jacob H.; Mendelev, Natalia; Brown, Trisha A; Tulis, David A.

doi:10.1124/jpet.111.183400

Cited by 46 publications

(106 citation statements)

References 35 publications

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“…Previously, we demonstrated in both rat commercial (A7R5) VSMCs and rat primary VSMCs that BAY increases cyclic nucleotides and inhibits vascular growth through processes involving VASP phosphorylation (Joshi et al, 2011;Mendelev et al, 2009). In this report we demonstrate for the first time that BAY increases the activity of protein kinases and that this system has the ability to regulate growth of VSMCs.…”

Section: Wwwintechopencommentioning

confidence: 64%

“…We recently demonstrated that BAY, a potent stimulator of sGC, increased phosphorylation of VASP in a site-specific fashion in rat A7R5 VSMCs and in rat primary VSMCs (Joshi et al, 2011). In the current study we sought to identify kinases responsible for this selective phosphorylation of VASP induced by BAY.…”

Section: The Effect Of Kinase Inhibitors On Bay-induced Vasp Phosphormentioning

confidence: 99%

“…Previously we observed that BAY inhibits cell migration in rat primary VSMCs (Joshi et al, 2011). In order to determine the role of kinases on this anti-migratory effect of BAY, VSMCs were pretreated with inhibitors of PKG, PKA or PKC prior to stimulation with BAY and migration was assessed using the wounding assay.…”

Section: Effect Of Kinase Inhibitors and Bay On Migrationmentioning

confidence: 99%

“…Previously we concluded that BAY inhibits proliferation of both rat A7R5 ) and rat primary VSMCs (Joshi et al, 2011). To determine the influence of kinases on BAY-induced growth suppression, three complementary assays were performed.…”

Section: Effect Of Kinase Inhibitors and Bay On Proliferationmentioning

confidence: 99%

“…Since BAY increases cAMP and cGMP (Joshi et al, 2011;Mendelev et al, 2009;Stasch et al, 2001;Stasch et al, 2009) as well as the activity of their respective kinases (Joshi et al, 2011), and considering that both kinases can phosphorylate VASP at either kinase-preferred site (Butt et al, 1994), cyclic nucleotide analogs were used to determine the kinase(s) specifically involved in VASP phosphorylation. VSMCs were incubated with selective kinase inhibitors prior to addition of a cAMP or cGMP analog.…”

Section: Effect Of Kinase Inhibitors On Cyclic Nucleotide Analog-indumentioning

confidence: 99%

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Multiple Kinase Involvement in the Regulation of Vascular Growth

Adderley¹,

Joshi²,

Martin³

et al. 2012

Advances in Protein Kinases

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Section: Wwwintechopencommentioning

confidence: 64%

Section: The Effect Of Kinase Inhibitors On Bay-induced Vasp Phosphormentioning

confidence: 99%

Section: Effect Of Kinase Inhibitors and Bay On Migrationmentioning

confidence: 99%

Section: Effect Of Kinase Inhibitors and Bay On Proliferationmentioning

confidence: 99%

Section: Effect Of Kinase Inhibitors On Cyclic Nucleotide Analog-indumentioning

confidence: 99%

See 3 more Smart Citations

Multiple Kinase Involvement in the Regulation of Vascular Growth

Adderley¹,

Joshi²,

Martin³

et al. 2012

Advances in Protein Kinases

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Soluble Guanylate Cyclase Stimulators in Pulmonary Hypertension

Stasch

Evgenov

2013

Handbook of Experimental Pharmacology

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Soluble guanylate cyclase (sGC) is a key enzyme in the nitric oxide (NO) signalling pathway. On binding of NO to its prosthetic haem group, sGC catalyses the synthesis of the second messenger cyclic guanosine monophosphate (cGMP), which promotes vasodilation and inhibits smooth muscle proliferation, leukocyte recruitment, platelet aggregation and vascular remodelling through a number of downstream mechanisms. The central role of the NO-sGC-cGMP pathway in regulating pulmonary vascular tone is demonstrated by the dysregulation of NO production, sGC activity and cGMP degradation in pulmonary hypertension (PH). The sGC stimulators are novel pharmacological agents that directly stimulate sGC, both independently of NO and in synergy with NO. Optimisation of the first sGC stimulator, YC-1, led to the development of the more potent and more specific sGC stimulators, BAY 41-2272, BAY 41-8543 and riociguat (BAY 63-2521). Other sGC stimulators include CFM-1571, BAY 60-4552, vericiguat (BAY 1021189), the acrylamide analogue A-350619 and the aminopyrimidine analogues. BAY 41-2272, BAY 41-8543 and riociguat induced marked dose-dependent reductions in mean pulmonary arterial pressure and vascular resistance with a concomitant increase in cardiac output, and they also reversed vascular remodelling and right heart hypertrophy in several experimental models of PH. Riociguat is the first sGC stimulator that has entered clinical development. Clinical trials have shown that it significantly improves pulmonary vascular haemodynamics and increases exercise ability in patients with pulmonary arterial hypertension (PAH), chronic thromboembolic PH and PH associated with interstitial lung disease. Furthermore, riociguat reduces mean pulmonary arterial pressure in patients with PH associated with chronic obstructive pulmonary disease and improves cardiac index and pulmonary vascular resistance in patients with PH associated with left ventricular systolic dysfunction. These promising results suggest that sGC stimulators may constitute a valuable new therapy for PH. Other trials of riociguat are in progress, including a study of the haemodynamic effects and safety of riociguat in patients with PH associated with left ventricular diastolic dysfunction, and long-term extensions of the phase 3 trials investigating the efficacy and safety of riociguat in patients with PAH and chronic thromboembolic PH. Finally, sGC stimulators may also have potential therapeutic applications in other diseases, including heart failure, lung fibrosis, scleroderma and sickle cell disease.

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