Cyclic GMP signaling in cardiovascular pathophysiology and therapeutics

Tsai, Emily J.; Kass, David A.

doi:10.1016/j.pharmthera.2009.02.009

Cited by 360 publications

(350 citation statements)

References 423 publications

(454 reference statements)

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“…Originally, work from Takimoto et al6 demonstrated the beneficial effects of PDE5 inhibition showing sildenafil attenuated hypertrophy, decreased fibrosis, and restored LV relaxation kinetics in aortic‐banded mice. Several preclinical and clinical studies followed investigating various methods of preserving cGMP levels, with beneficial results 5, 9, 10, 15, 44, 45, 46. However, the sole multicenter study targeting this signaling in HFpEF, the RELAX trial (Effect of Phosphodiesterase‐5 Inhibition on Exercise Capacity and Clinical Status in Heart Failure with Preserved Ejection Fraction), reported equivocal results after testing the PDE5 inhibitor sildenafil 47.…”

Section: Discussionmentioning

confidence: 99%

“…Cyclic guanosine monophosphate (cGMP) levels modulate many signaling pathways regulating diastolic function and may inhibit ventricular hypertrophy and stiffness while promoting diastolic relaxation 5, 6, 7, 8. There is growing evidence the cGMP signaling cascade is disturbed in HFpEF patients and could contribute to diastolic dysfunction 4, 5, 9, 10. cGMP signaling may be reduced in HF via 3 primary cellular mechanisms: (1) enhanced catabolism through upregulation of specific phosphodiesterases (PDEs); (2) decreased synthesis via impaired natriuretic peptide activation of transmembrane‐associated particulate guanylate cyclase receptors; or (3) decreased nitric oxide (NO) stimulation of and/or responsiveness by soluble guanylate cyclase 5…”

Section: Introductionmentioning

confidence: 99%

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Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic‐Banded Mini‐Swine

Hiemstra

Lee

Chakir

et al. 2016

JAHA

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BackgroundCyclic guanosine monophosphate‐protein kinase G‐phosphodiesterase 5 signaling may be disturbed in heart failure (HF) with preserved ejection fraction, contributing to cardiac remodeling and dysfunction. The purpose of this study was to manipulate cyclic guanosine monophosphate signaling using the dipeptidyl‐peptidase 4 inhibitor saxagliptin and phosphodiesterase 5 inhibitor tadalafil. We hypothesized that preservation of cyclic guanosine monophosphate cGMP signaling would attenuate pathological cardiac remodeling and improve left ventricular (LV) function.Methods and ResultsWe assessed LV hypertrophy and function at the organ and cellular level in aortic‐banded pigs. Concentric hypertrophy was equal in all groups, but LV collagen deposition was increased in only HF animals. Prevention of fibrotic remodeling by saxagliptin and tadalafil was correlated with neuropeptide Y plasma levels. Saxagliptin better preserved integrated LV systolic and diastolic function by maintaining normal LV chamber volumes and contractility (end‐systolic pressure‐volume relationship, preload recruitable SW) while preventing changes to early/late diastolic longitudinal strain rate. Function was similar to the HF group in tadalafil‐treated animals including increased LV contractility, reduced chamber volume, and decreased longitudinal, circumferential, and radial mechanics. Saxagliptin and tadalafil prevented a negative cardiomyocyte shortening‐frequency relationship observed in HF animals. Saxagliptin increased phosphodiesterase 5 activity while tadalafil increased cyclic guanosine monophosphate levels; however, neither drug increased downstream PKG activity. Early mitochondrial dysfunction, evident as decreased calcium‐retention capacity and Complex II‐dependent respiratory control, was present in both HF and tadalafil‐treated animals.ConclusionsBoth saxagliptin and tadalafil prevented increased LV collagen deposition in a manner related to the attenuation of increased plasma neuropeptide Y levels. Saxagliptin appears superior for treating heart failure with preserved ejection fraction, considering its comprehensive effects on integrated LV systolic and diastolic function.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic‐Banded Mini‐Swine

Hiemstra

Lee

Chakir

et al. 2016

JAHA

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“…Conversely, it is well-documented that nitric oxide (NO), cyclic GMP (cGMP), and protein kinase G (PKG) signaling pathway have a "brake-like" negatively regulatory role in cardiac hypertrophy [6,11]. Along this line, sildenafil, a cGMP-phosphodiesterase inhibitor that raises cytosolic cGMP level and thus stimulates PKG, has been shown to ameliorate cardiac hypertrophy and remodeling [6].…”

Section: Introductionmentioning

confidence: 99%

Nitric Oxide-cGMP-PKG Pathway Acts on Orai1 to Inhibit the Hypertrophy of Human Embryonic Stem Cell-Derived Cardiomyocytes

Wang

Zhang

et al. 2015

Stem Cells

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Cardiac hypertrophy is an abnormal enlargement of heart muscle. It frequently results in congestive heart failure, which is a leading cause of human death. Previous studies demonstrated that the nitric oxide (NO), cyclic GMP (cGMP), and protein kinase G (PKG) signaling pathway can inhibit cardiac hypertrophy and thus improve cardiac function. However, the underlying mechanisms are not fully understood. Here, based on the human embryonic stem cell-derived cardiomyocyte (hESC-CM) model system, we showed that Orai1, the pore-forming subunit of store-operated Ca 21 entry (SOCE), is the downstream effector of PKG. Treatment of hESC-CMs with an a-adrenoceptor agonist phenylephrine (PE) caused a marked hypertrophy, which was accompanied by an upregulation of Orai1. Moreover, suppression of Orai1 expression/activity using Orai1-siRNAs or a dominant-negative construct Orai1 G98A inhibited the hypertrophy, suggesting that Orai1-mediated SOCE is indispensable for the PE-induced hypertrophy of hESC-CMs. In addition, the hypertrophy was inhibited by NO and cGMP via activating PKG. Importantly, substitution of Ala for Ser 34 in Orai1 abolished the antihypertrophic effects of NO, cGMP, and PKG. Furthermore, PKG could directly phosphorylate Orai1 at Ser 34 and thus prevent Orai1-mediated SOCE. Together, we conclude that NO, cGMP, and PKG inhibit the hypertrophy of hESC-CMs via PKG-mediated phosphorylation on Orai1-Ser-34. These results provide novel mechanistic insights into the action of cGMP-PKG-related antihypertrophic agents, such as NO donors and sildenafil. STEM CELLS 2015;33:2973-2984 SIGNIFICANCE STATEMENTCardiac hypertrophy is an abnormal enlargement of cardiomyocytes. It contributes to congestive heart failure. Nitric oxide donors and cGMP-phosphodiesterase inhibitors have been used in clinical trials to treat cardiac hypertrophy. However, the underlying mechanisms of these agents are not fully understood. Here, with the use of human embryonic stem cell-derived cardiomyocytes as the model, we uncovered a novel mechanism underlying the inhibitory effect of these agents on cardiac hypertrophy. We found that nitric oxide and cGMP, via protein kinase G-mediated phosphorylation on Orai1 proteins, inhibit the cardiomyocyte hypertrophy. This study provides novel mechanistic insights into the action of nitric oxide-related anti-hypertrophic agents.

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“…On the other hand, NO signaling is also an important modulator of cardiac function. NO stimulates GC1 to produce cGMP, which negatively regulates cardiomyocyte contractility by modulation of calcium homeostasis via protein kinase G–dependent phosphorylation 14, 30…”

Section: Discussionmentioning

confidence: 99%

“…In specific microdomains, cGMP can modulate cAMP signaling by activation or inhibition of cAMP breakdown by phosphodiesterases 2 and 3, respectively. The organization in microdomains and the cAMP/cGMP interplay are areas under intense investigation because disruption of the cAMP/cGMP spatiotemporal distribution is associated with cardiac dysfunction 13, 14. Our initial observation that GC1 was located at the ID and the novel finding of its proximity to Cx43 prompted us to investigate the potential function of the NO‐cGMP pathway in relation to Cx43 function.…”

mentioning

confidence: 99%

Newly Identified NO‐Sensor Guanylyl Cyclase/Connexin 43 Association Is Involved in Cardiac Electrical Function

Crassous

Shu

Huang

et al. 2017

JAHA

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BackgroundGuanylyl cyclase, a heme‐containing α1β1 heterodimer (GC1), produces cGMP in response to Nitric oxide (NO) stimulation. The NO‐GC1‐cGMP pathway negatively regulates cardiomyocyte contractility and protects against cardiac hypertrophy–related remodeling. We recently reported that the β1 subunit of GC1 is detected at the intercalated disc with connexin 43 (Cx43). Cx43 forms gap junctions (GJs) at the intercalated disc that are responsible for electrical propagation. We sought to determine whether there is a functional association between GC1 and Cx43 and its role in cardiac homeostasis.Methods and Results GC1 and Cx43 immunostaining at the intercalated disc and coimmunoprecipitation from membrane fraction indicate that GC1 and Cx43 are associated. Mice lacking the α subunit of GC1 (GCα1 knockout mice) displayed a significant decrease in GJ function (dye‐spread assay) and Cx43 membrane lateralization. In a cardiac‐hypertrophic model, angiotensin II treatment disrupted the GC1‐Cx43 association and induced significant Cx43 membrane lateralization, which was exacerbated in GCα1 knockout mice. Cx43 lateralization correlated with decreased Cx43‐containing GJs at the intercalated disc, predictors of electrical dysfunction. Accordingly, an ECG revealed that angiotensin II–treated GCα1 knockout mice had impaired ventricular electrical propagation. The phosphorylation level of Cx43 at serine 365, a protein‐kinase A upregulated site involved in trafficking/assembly of GJs, was decreased in these models.Conclusions GC1 modulates ventricular Cx43 location, hence GJ function, and partially protects from electrical dysfunction in an angiotensin II hypertrophy model. Disruption of the NO‐cGMP pathway is associated with cardiac electrical disturbance and abnormal Cx43 phosphorylation. This previously unknown NO/Cx43 signaling could be a protective mechanism against stress‐induced arrhythmia.

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Cyclic GMP signaling in cardiovascular pathophysiology and therapeutics

Cited by 360 publications

References 423 publications

Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic‐Banded Mini‐Swine

Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic‐Banded Mini‐Swine

Nitric Oxide-cGMP-PKG Pathway Acts on Orai1 to Inhibit the Hypertrophy of Human Embryonic Stem Cell-Derived Cardiomyocytes

Newly Identified NO‐Sensor Guanylyl Cyclase/Connexin 43 Association Is Involved in Cardiac Electrical Function

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