Transcriptional and post-transcriptional regulation of cGMP-dependent protein kinase (PKG-I): pathophysiological significance

Hassan, Sazzad; Choi, Chung Sik; Dey, Nupur B.; Lincoln, Thomas M.

doi:10.1093/cvr/cvs327

Cited by 29 publications

(21 citation statements)

References 109 publications

(74 reference statements)

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“…PKGmediated blockage of mitochondrial permeability transition and cytochrome c release plays a key role in nitric oxide's protection effect on the ischemic heart. In addition, PKGdependent ERK phosphorylation is indispensable for the induction of endothelial and inducible nitric oxide synthase and Bcl-2 and the resulting cardioprotection by sildenafil, a selective inhibitor of PDE type 5, which exerts degradation of cGMP (6,30). Here, we demonstrated for the first time that the VNP-cGMP-PKG1 signaling pathway mediates VNP's inhibition of ER stress and apoptosis both in vivo and in vitro and inhibition of oxidative stress is involved in this effect.…”

Section: Discussionmentioning

confidence: 68%

Vasonatrin peptide attenuates myocardial ischemia-reperfusion injury in diabetic rats and underlying mechanisms

Shi

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Diabetes mellitus increases morbidity/mortality of ischemic heart disease. Although atrial natriuretic peptide and C-type natriuretic peptide reduce the myocardial ischemia-reperfusion damage in nondiabetic rats, whether vasonatrin peptide (VNP), the artificial synthetic chimera of atrial natriuretic peptide and C-type natriuretic peptide, confers cardioprotective effects against ischemia-reperfusion injury, especially in diabetic patients, is still unclear. This study was designed to investigate the effects of VNP on ischemia-reperfusion injury in diabetic rats and to further elucidate its mechanisms. The high-fat diet-fed streptozotocin-induced diabetic Sprague-Dawley rats were subjected to ischemia-reperfusion operation. VNP treatment (100 μg/kg iv, 10 min before reperfusion) significantly improved the instantaneous first derivation of left ventricle pressure (±LV dP/dtmax) and LV systolic pressure and reduced LV end-diastolic pressure, apoptosis index, caspase-3 activity, plasma creatine kinase (CK), and lactate dehydrogenase (LDH) activities. Moreover, VNP inhibited endoplasmic reticulum (ER) stress by suppressing glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP). These effects were mimicked by 8-bromine-cyclic guanosinemonophosphate (8-Br-cGMP), a cGMP analog, whereas they were inhibited by KT-5823, the selective inhibitor of PKG. In addition, pretreatment with tauroursodeoxycholic acid (TUDCA), a specific inhibitor of ER stress, could not further promote the VNP's cardioprotective effect in diabetic rats. In vitro H9c2 cardiomyocytes were subjected to hypoxia/reoxygenation and incubated with or without VNP (10(-8) mol/l). Gene knockdown of PKG1α with siRNA blunted VNP inhibition of ER stress and apoptosis, while overexpression of PKG1α resulted in significant decreased ER stress and apoptosis. VNP protects the diabetic heart against ischemia-reperfusion injury by inhibiting ER stress via the cGMP-PKG signaling pathway. These results suggest that VNP may have potential therapeutic value for the diabetic patients with ischemic heart disease.

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Section: Discussionmentioning

confidence: 68%

Vasonatrin peptide attenuates myocardial ischemia-reperfusion injury in diabetic rats and underlying mechanisms

Shi

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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“…We finally examined the expressions of BK Ca subunits and PKG, a major down-stream pathway of cGMP, 48,49) in carotid arteries by Western blotting analysis (Fig. 5).…”

Section: Expression Of Bk Ca and Pkg-1 In Carotid Arterymentioning

confidence: 99%

Relaxation Induced by Atrial Natriuretic Peptide Is Impaired in Carotid but Not Renal Arteries from Spontaneously Hypertensive Rats Due to Reduced BK<sub>Ca</sub> Channel Activity

Matsumoto

Watanabe

Yamada

et al. 2015

Biological & Pharmaceutical Bulletin

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Atrial natriuretic peptide (ANP) plays an important role in vascular functions such as blood pressure regulation and relaxant activity. Individual vascular beds exhibit differences in vascular reactivity to various ligands, however, the difference in responsiveness to ANP between carotid and renal arteries and the molecular mechanisms of its vasorelaxant activity in a pathophysiological state, including hypertension, remain unclear. We therefore investigated this issue by exposing carotid and renal artery rings obtained from spontaneously hypertensive rats (SHR) to ANP. In the SHR artery (vs. control WKY artery), the ANP-induced relaxations were reduced in carotid artery but not renal artery. Acetylcholine-induced relaxations were reduced in both arteries in SHR (vs. WKY). Sodium nitroprusside-induced relaxation was similar in both arteries between the groups. In carotid arteries, the ANP-induced relaxation was not affected by endothelial denudation or by treatment with inhibitors of nitric oxide synthase, cyclooxygenase, the voltage-dependent potassium channel, or ATP-sensitive potassium channel in arteries from both SHR and WKY. In the carotid artery from WKY but not SHR, the ANP-induced relaxation was significantly reduced by inhibition of the large-conductance calcium-activated potassium channel (BK Ca ). The BK Ca activator-induced relaxation was reduced in the SHR artery (vs. WKY). These results suggest that ANP-induced relaxation is impaired in the carotid artery from SHR and this impairment may be at least in part due to the reduction of BK Ca activity rather than endothelial components.Key words atrial natriuretic peptide (ANP); carotid artery; potassium channel; relaxation; spontaneously hypertensive rat (SHR) Hypertension contributes markedly to global cardiovascular morbidity and mortality.1-3) Vascular dysfunction is a hallmark of hypertension and frequently leads to the development of atherosclerosis, stroke, and peripheral arterial disease.1,4) In vascular dysfunction, abnormalities of vascular smooth muscle cells and endothelial cells are key factors in the development of hypertension-associated vascular complications. 5-7)It has been shown that endogenous vasoactive peptides such as angiotensin II, endothelin-1, urotensin II, and natriuretic peptides play an important role in the regulation of vascular tone in (patho) physiological conditions. 8-11) Several reports suggested that the signalings of vasoactive peptides, including their production, metabolism, and affected vascular functions, are altered in arteries from hypertensive patients and animal models.6,10,12) Therefore, the manipulation of vasoactive peptide signaling is one of the most important strategies against the development of vascular dysfunction in hypertension.Atrial natriuretic peptide (ANP) has received particular attention since its effects on the cardiac function and blood pressure regulation have been reported through various mechanisms, including diuretic, natriuretic, and vasorelaxation. [13][14][15][16][17][18][19][20][2...

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“…Hence, we therefore restricted our studies to low passage number cells and ensured fully functional cGK-I signaling by validating that the NO donor, DETA-NO, the cGK-I activator, 8-Br-cGMP, or the NO-independent Fe(II)sGC stimulator were able to reduce cGK-I expression (Fig. 3A), an expressional regulation known to be cGMP/cGK-I-dependent (27).…”

Section: Resultsmentioning

confidence: 99%

A non-canonical chemical feedback self-limits nitric oxide-cyclic GMP signaling in health and disease

Dao

Elbatreek

Deile³

et al. 2018

Preprint

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(240 words)Endothelial nitric oxide (NO) stimulates the heme protein, soluble guanylyl cyclase (sGC) to form vasoprotective cyclic GMP (cGMP). In different disease states such as pulmonary hypertension, NO-cGMP signaling is pharmacologically augmented, yet the pathomechanisms leading to its dysregulation are incompletely understood. Here we show in pulmonary artery endothelial cells that endogenous NO or NO donor compounds acutely stimulate sGC activity, but chronically down-regulate both sGC protein and cGMP formation. Surprisingly, this endogenous feedback mechanism was independent of canonical cGMP signaling via cGMPdependent protein kinase. It did not involve thiol-dependent modulation, a process relevant for sGC maturation, either. Rather tonic NO exposure led to inactivation and degradation of NOsGC and without affecting NO-insensitive apo-sGC levels. Apo-sGC could be re-activated pharmacologically by the heme mimetic class of so-called sGC activators. Importantly, this noncanonical feedback was also observed in vivo. Specifically, it was induced by pathological high levels of NO in acute respiratory distress syndrome in which a similar self-limiting redox shift from NO-sensitive sGC to NO-insensitive apo-sGC occurred. Thus, our data establish a bimodal mechanism by which NO acutely stimulates sGC and chronically decreases sGC levels as part of a physiological and pathological self-limiting feedback. Of therapeutic importance in disease, our findings i) caution against any chronic use of classical NO donor drugs and ii) suggest that high NO-induced apo-sGC can be functionally fully recovered by sGC activator drugs to reestablish cGMP formation.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/383208 doi: bioRxiv preprint first posted online Aug. 2, 2018; 3 Significance Statement (122 of 120) Dysfunctional nitric oxide (NO) signaling via the cyclic GMP (cGMP) forming heme-protein soluble guanylate cyclase (sGC) is a key cardiopulmonary disease mechanism. However, in particular during chronic use, NO donor drugs display limited therapeutic benefit. Here we identify a previously unrecognized non-canonical chemical feedback mechanism, which selflimits cGMP formation in response to NO donor drugs and endogenous NO, both in health and disease. Whilst NO acutely stimulates sGC, we find that exposure of sGC to either chronic NO or pathological NO overproduction reduces sGC and generates heme-free apo-sGC which is insensitive to NO but sensitive to heme-mimetic sGC activators. Importantly, this chemical feedback explains the limited applicability of NO-donor drugs for chronic treatment and explain their mechanism-based indication in vascular disease conditions.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to displ...

show abstract

Transcriptional and post-transcriptional regulation of cGMP-dependent protein kinase (PKG-I): pathophysiological significance

Cited by 29 publications

References 109 publications

Vasonatrin peptide attenuates myocardial ischemia-reperfusion injury in diabetic rats and underlying mechanisms

Vasonatrin peptide attenuates myocardial ischemia-reperfusion injury in diabetic rats and underlying mechanisms

Relaxation Induced by Atrial Natriuretic Peptide Is Impaired in Carotid but Not Renal Arteries from Spontaneously Hypertensive Rats Due to Reduced BK<sub>Ca</sub> Channel Activity

A non-canonical chemical feedback self-limits nitric oxide-cyclic GMP signaling in health and disease

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