scholarly journals Phosphodiesterase 5 Inhibition Limits Doxorubicin-induced Heart Failure by Attenuating Protein Kinase G Iα Oxidation

2016 ◽  
Vol 291 (33) ◽  
pp. 17427-17436 ◽  
Author(s):  
Oleksandra Prysyazhna ◽  
Joseph Robert Burgoyne ◽  
Jenna Scotcher ◽  
Steven Grover ◽  
David Kass ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Pde5 Inhibitor ◽  
Cardiac Injury ◽  
Left Ventricular ◽  
Loss Of Function ◽  
Doxorubicin Treatment ◽  
Disulfide Formation ◽  
Additional Protection ◽  
Phosphodiesterase 5

Phosphodiesterase 5 (PDE5) inhibitors limit myocardial injury caused by stresses, including doxorubicin chemotherapy. cGMP binding to PKG Iα attenuates oxidant-induced disulfide formation. Because PDE5 inhibition elevates cGMP and protects from doxorubicin-induced injury, we reasoned that this may be because it limits PKG Iα disulfide formation. To investigate the role of PKG Iα disulfide dimerization in the development of apoptosis, doxorubicin-induced cardiomyopathy was compared in male wild type (WT) or disulfide-resistant C42S PKG Iα knock-in (KI) mice. Echocardiography showed that doxorubicin treatment caused loss of myocardial tissue and depressed left ventricular function in WT mice. Doxorubicin also reduced pro-survival signaling and increased apoptosis in WT hearts. In contrast, KI mice were markedly resistant to the dysfunction induced by doxorubicin in WTs. In follow-on experiments the influence of the PDE5 inhibitor tadalafil on the development of doxorubicin-induced cardiomyopathy in WT and KI mice was investigated. In WT mice, co-administration of tadalafil with doxorubicin reduced PKG Iα oxidation caused by doxorubicin and also protected against cardiac injury and loss of function. KI mice were again innately resistant to doxorubicin-induced cardiotoxicity, and therefore tadalafil afforded no additional protection. Doxorubicin decreased phosphorylation of RhoA (Ser-188), stimulating its GTPase activity to activate Rho-associated protein kinase (ROCK) in WTs. These pro-apoptotic events were absent in KI mice and were attenuated in WTs co-administered tadalafil. PKG Iα disulfide formation triggers cardiac injury, and this initiation of maladaptive signaling can be blocked by pharmacological therapies that elevate cGMP, which binds kinase to limit its oxidation.

scholarly journals Phosphodiesterase 5 inhibition ameliorates angiontensin II-induced podocyte dysmotility via the protein kinase G-mediated downregulation of TRPC6 activity

2014 ◽  
Vol 306 (12) ◽  
pp. F1442-F1450 ◽  
Author(s):  
Gentzon Hall ◽  
Janelle Rowell ◽  
Federica Farinelli ◽  
Rasheed A. Gbadegesin ◽  
Peter Lavin ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Soluble Guanylate Cyclase ◽  
Pde5 Inhibitor ◽  
Receptor Potential ◽  
Nitric Oxide Donor ◽  
Ang Ii ◽  
Calcineurin Phosphatase ◽  
Phosphodiesterase 5

The emerging role of the transient receptor potential cation channel isotype 6 (TRPC6) as a central contributor to various pathological processes affecting podocytes has generated interest in the development of therapeutics to modulate its function. Recent insights into the regulation of TRPC6 have revealed PKG as a potent negative modulator of TRPC6 conductance and associated signaling via its phosphorylation at two highly conserved amino acid residues: Thr69/Thr70 (Thr69 in mice and Thr70 in humans) and Ser321/Ser322 (Ser321 in mice and Ser322 in humans). Here, we tested the role of PKG in modulating TRPC6-dependent responses in primary and conditionally immortalized mouse podocytes. TRPC6 was phosphorylated at Thr69 in nonstimulated podocytes, but this declined upon ANG II stimulation or overexpression of constitutively active calcineurin phosphatase. ANG II induced podocyte motility in an in vitro wound assay, and this was reduced 30–60% in cells overexpressing a phosphomimetic mutant TRPC6 (TRPC6T70E/S322E) or activated PKG ( P < 0.05). Pretreatment of podocytes with the PKG agonists S-nitroso- N-acetyl-dl-penicillamine (nitric oxide donor), 8-bromo-cGMP, Bay 41–2772 (soluble guanylate cyclase activator), or phosphodiesterase 5 (PDE5) inhibitor 4-{[3′,4′-(methylenedioxy)benzyl]amino}[7]-6-methoxyquinazoline attenuated ANG II-induced Thr69 dephosphorylation and also inhibited TRPC6-dependent podocyte motility by 30–60%. These data reveal that PKG activation strategies, including PDE5 inhibition, ameliorate ANG II-induced podocyte dysmotility by targeting TRPC6 in podocytes, highlighting the potential therapeutic utility of these approaches to treat hyperactive TRPC6-dependent glomerular disease.

scholarly journals Conventional protein kinase C in the brain: 40 years later

2017 ◽  
Vol 1 (2) ◽  
Author(s):  
Julia A. Callender ◽  
Alexandra C. Newton
Keyword(s):  
Cell Death ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Loss Of Function ◽  
Membrane Phospholipids ◽  
Kinase C ◽  
Pkc Isozymes ◽  
Hydrolysis Of ◽  
The Brain

Protein kinase C (PKC) is a family of enzymes whose members transduce a large variety of cellular signals instigated by the receptor-mediated hydrolysis of membrane phospholipids. While PKC has been widely implicated in the pathology of diseases affecting all areas of physiology including cancer, diabetes, and heart disease—it was discovered, and initially characterized, in the brain. PKC plays a key role in controlling the balance between cell survival and cell death. Its loss of function is generally associated with cancer, whereas its enhanced activity is associated with neurodegeneration. This review presents an overview of signaling by diacylglycerol (DG)-dependent PKC isozymes in the brain, and focuses on the role of the Ca2+-sensitive conventional PKC isozymes in neurodegeneration.

Role of biomarkers in cardioncology

2011 ◽  
Vol 49 (12) ◽  
Author(s):  
Daniela Cardinale ◽  
Michela Salvatici ◽  
Maria T. Sandri
Keyword(s):  
Troponin I ◽  
Cardiac Injury ◽  
Left Ventricular ◽  
Cardiac Biomarkers ◽  
Left Ventricular Ejection ◽  
Cardiac Events ◽  
Current Standard ◽  
Converting Enzyme Inhibitors ◽  
Ventricular Ejection Fraction

AbstractCardiotoxicity is a serious adverse effect of anticancer drugs, impacting on quality of life and overall survival of cancer patients. According to the current standard for monitoring cardiac function, cardiotoxicity is usually detected only when a functional impairment has already occurred, precluding any chance of preventing its development. Over the last decade, however, a new approach, based on the use of cardiac biomarkers, has emerged, and has proven to be an effective alternative strategy for early detection of subclinical cardiac injury. In particular, the role of troponin I in identifying patients at risk of cardiotoxicity and of angiotensin-converting enzyme inhibitors in preventing left ventricular ejection fraction reduction and late cardiac events represent an effective tool for the prevention of this complication.

Platelet-activating factor induces cardioprotection in isolated rat heart akin to ischemic preconditioning: role of phosphoinositide 3-kinase and protein kinase C activation

2005 ◽  
Vol 288 (5) ◽  
pp. H2512-H2520 ◽  
Author(s):  
Claudia Penna ◽  
Giuseppe Alloatti ◽  
Sandra Cappello ◽  
Donatella Gattullo ◽  
Giovanni Berta ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Ischemic Preconditioning ◽  
Platelet Activating Factor ◽  
Left Ventricular ◽  
Isolated Rat Heart ◽  
Cardioprotective Effect ◽  
Kinase C ◽  
Phosphoinositide 3 Kinase

Ischemic preconditioning (IP) is a cardioprotective mechanism against myocellular death and cardiac dysfunction resulting from reperfusion of the ischemic heart. At present, the precise list of mediators involved in IP and the pathways of their mechanisms of action are not completely known. The aim of the present study was to investigate the role of platelet-activating factor (PAF), a phospholipid mediator that is known to be released by the ischemic-reperfused heart, as a possible endogenous agent involved in IP. Experiments were performed on Langendorff-perfused rat hearts undergoing 30 min of ischemia followed by 2 h of reperfusion. Treatment with a low concentration of PAF (2 × 10−11 M) before ischemia reduced the extension of infarct size and improved the recovery of left ventricular developed pressure during reperfusion. The cardioprotective effect of PAF was comparable to that observed in hearts in which IP was induced by three brief (3 min) periods of ischemia separated by 5-min reperfusion intervals. The PAF receptor antagonist WEB-2170 (1 × 10−9 M) abrogated the cardioprotective effect induced by both PAF and IP. The protein kinase C (PKC) inhibitor chelerythrine (5 × 10−6 M) or the phosphoinositide 3-kinase (PI3K) inhibitor LY-294002 (5 × 10−5 M) also reduced the cardioprotective effect of PAF. Western blot analysis revealed that following IP treatment or PAF infusion, the phosphorylation of PKC-ε and Akt (the downstream target of PI3K) was higher than that in control hearts. The present data indicate that exogenous applications of low quantities of PAF induce a cardioprotective effect through PI3K and PKC activation, similar to that afforded by IP. Moreover, the study suggests that endogenous release of PAF, induced by brief periods of ischemia and reperfusion, may participate to the triggering of the IP of the heart.

scholarly journals Phosphodiesterase-5 inhibitors and the heart: compound cardioprotection?

Heart ◽  
2018 ◽  
Vol 104 (15) ◽  
pp. 1244-1250 ◽  
Author(s):  
David Charles Hutchings ◽  
Simon George Anderson ◽  
Jessica L Caldwell ◽  
Andrew W Trafford
Keyword(s):  
Clinical Trials ◽  
Contractile Function ◽  
Myocardial Infarct ◽  
Pde5 Inhibitor ◽  
Left Ventricular ◽  
Myocardial Infarct Size ◽  
Protective Effects ◽  
Pde5 Inhibitors ◽  
Treatment Benefit ◽  
Phosphodiesterase 5

Novel cardioprotective agents are needed in both heart failure (HF) and myocardial infarction. Increasing evidence from cellular studies and animal models indicate protective effects of phosphodiesterase-5 (PDE5) inhibitors, drugs usually reserved as treatments of erectile dysfunction and pulmonary arterial hypertension. PDE5 inhibitors have been shown to improve contractile function in systolic HF, regress left ventricular hypertrophy, reduce myocardial infarct size and suppress ischaemia-induced ventricular arrhythmias. Underpinning these actions are complex but increasingly understood cellular mechanisms involving the cyclic GMP activation of protein kinase-G in both cardiac myocytes and the vasculature. In clinical trials, PDE5 inhibitors improve symptoms and ventricular function in systolic HF, and accumulating epidemiological data indicate a reduction in cardiovascular events and mortality in PDE5 inhibitor users at high cardiovascular risk. Here, we focus on the translation of underpinning basic science to clinical studies and report that PDE5 inhibitors act through a number of cardioprotective mechanisms, including a direct myocardial action independent of the vasculature. We conclude that future clinical trials should be designed with these mechanisms in mind to identify patient subsets that derive greatest treatment benefit from these novel cardioprotective agents.

Inhibition of sphingomyelin synthase 2 relieves hypoxia-induced cardiomyocyte injury by reinforcing Nrf2/ARE activation via modulation of GSK-3β

2020 ◽  
pp. 096032712096995
Author(s):  
Aiping Jin ◽  
Haijuan Cheng ◽  
Lina Xia ◽  
Sha Ye ◽  
Cuiling Yang
Keyword(s):  
Myocardial Infarction ◽  
Potential Role ◽  
Glycogen Synthase ◽  
Tissue Injury ◽  
Cardiac Injury ◽  
Ros Generation ◽  
Related Factor ◽  
Loss Of Function ◽  
Sphingomyelin Synthase

Sphingomyelin synthase 2 (SMS2) is a vital contributor to tissue injury and affects various pathological processes. However, whether SMS2 participates in the modulation of cardiac injury in myocardial infarction has not been determined. This study aimed to evaluate the potential role of SMS2 in the regulation of cardiomyocyte injury induced by hypoxia, an in vitro model for studying myocardial infarction. Our data revealed that SMS2 expression was significantly upregulated in cardiomyocytes in response to hypoxia. Loss-of-function experiments revealed that knockdown of SMS2 markedly restored the viability of cardiomyocytes impaired by hypoxia, and attenuated hypoxia-evoked apoptosis and reactive oxygen species (ROS) generation. In contrast, cardiomyocytes that highly expressed SMS2 were more sensitive to hypoxia-induced injury. Moreover, SMS2 deficiency enhanced the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling through inactivation of glycogen synthase kinase-3β. Notably, suppression of Nrf2 markedly abrogated SMS2 knockdown-mediated cardioprotective effects on hypoxia-exposed cardiomyocytes. Our results illustrate that downregulation of SMS2 exerts a cardioprotective function by protecting cardiomyocytes from hypoxia-induced apoptosis and oxidative stress through enhancement of Nrf2 activation. Our study indicates a potential role of SMS2 in the modulation of cardiac injury, which may contribute to the progression of myocardial infarction.

scholarly journals HMGB1 Aggravates Pressure Overload-Induced Left Ventricular Dysfunction by Promoting Myocardial Fibrosis

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Lei Zhang ◽  
Ying Yu ◽  
Peng Yu ◽  
Jian Wu ◽  
Aijun Sun ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Collagen Type ◽  
Cardiac Injury ◽  
Pressure Overload ◽  
High Mobility ◽  
Collagen Type I ◽  
Left Ventricular ◽  
Type I ◽  
Lv Dysfunction

Aim. Fibrosis had important effects on pressure overload-induced left ventricular (LV) dysfunction. High-mobility group box 1 (HMGB1), which was closely associated with fibrosis, was involved in the pressure overload-induced cardiac injury. This study determines the role of HMGB1 in LV dysfunction under pressure overload. Methods. Transverse aortic constriction (TAC) operation was performed on male C57BL/6J mice to build the model of pressure overload, while HMGB1 or PBS was injected into the LV wall. Cardiac function, collagen volume, and relevant genes were detected. Results. Echocardiography demonstrated that the levels of LV ejection fraction (LVEF) were markedly decreased on day 28 after TAC, which was consistent with raised collagen in the myocardium. Moreover, we found that the exposure of mice to TAC + HMGB1 is associated with higher mortality, BNP, and collagen volume in the myocardium and lower LVEF. In addition, real-time PCR showed that the expression of collagen type I, TGF-β, and MMP2 markedly increased in the myocardium after TAC, while HMGB1 overexpression further raised the TGF-β expression but not collagen type I and MMP2 expressions. Conclusion. This study indicated that exogenous HMGB1 overexpression in the myocardium aggravated the pressure overload-induced LV dysfunction by promoting cardiac fibrosis, which may be mediated by increasing the TGF-β expression.

scholarly journals Oxidation of Protein Kinase A Regulatory Subunit PKARIα Protects Against Myocardial Ischemia-Reperfusion Injury by Inhibiting Lysosomal-Triggered Calcium Release

Circulation ◽  
2020 ◽  
Author(s):  
Jillian N. Simon ◽  
Besarte Vrellaku ◽  
Stefania Monterisi ◽  
Sandy M. Chu ◽  
Nadiia Rawlings ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Cellular Localization ◽  
Calcium Release ◽  
Left Ventricular ◽  
Stimulated Emission ◽  
Disulfide Formation ◽  
The Impact ◽  
Kinase A

Background: Kinase oxidation is a critical signalling mechanism through which changes in the intracellular redox state alter cardiac function. In the myocardium, type-1 protein kinase A (PKARIα) can be reversibly oxidized, forming interprotein disulfide bonds within the holoenzyme complex. However, the effect of PKARIα disulfide formation on downstream signaling in the heart, particularly under states of oxidative stress such as ischemia and reperfusion (I/R), remains unexplored. Methods: Atrial tissue obtained from patients before and after cardiopulmonary bypass and reperfusion and left ventricular (LV) tissue from mice subjected to I/R or sham surgery were used to assess PKARIα disulfide formation by immunoblot. To determine the impact of disulfide formation on PKARIα catalytic activity and sub-cellular localization, live-cell fluorescence imaging and stimulated emission depletion super-resolution microscopy were performed in prkar1 knock-out mouse embryonic fibroblasts, neonatal myocytes or adult LV myocytes isolated from 'redox dead' (Cys17Ser) PKARIα knock-in mice and their wild-type littermates. Comparison of intracellular calcium dynamics between genotypes was assessed in fura2-loaded LV myocytes whereas I/R-injury was assessed ex vivo. Results: In both humans and mice, myocardial PKARIα disulfide formation was found to be significantly increased (2-fold in humans, p=0.023; 2.4-fold in mice, p<0.001) in response to I/R in vivo. In mouse LV cardiomyocytes, disulfide-containing PKARIα was not found to impact catalytic activity, but instead led to enhanced A-kinase-anchoring protein (AKAP) binding with preferential localization of the holoenzyme to the lysosome. Redox-dependent regulation of lysosomal two pore channels (TPC) by PKARIα was sufficient to prevent global calcium release from the sarcoplasmic reticulum in LV myocytes, without affecting intrinsic ryanodine receptor leak or phosphorylation. Absence of I/R-induced PKARIα disulfide formation in "redox dead" knock-in mouse hearts resulted in larger infarcts (2-fold, p<0.001) and a concomitant reduction in LV contractile recovery (1.6-fold, p<0.001), which was prevented by administering the lysosomal TPC inhibitor Ned-19 at the time of reperfusion. Conclusions: Disulfide-modification targets PKARIα to the lysosome where it acts as a gatekeeper for TPC-mediated triggering of global calcium release. In the post-ischemic heart, this regulatory mechanism is critical for protecting from extensive injury and offers a novel target for the design of cardioprotective therapeutics.

P3488Mechanistic insight on the cardioprotective effect of levosimendan against doxorubicin induced cardiomyopathy: Pivotal role of PKA signaling

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
P Efentakis ◽  
A Varela ◽  
D Sanoudou ◽  
C Davos ◽  
A Klinakis ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Left Ventricular ◽  
Cardioprotective Effect ◽  
In Vivo Model ◽  
Dependent Manner ◽  
Clinical Investigations ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Abstract Background Levosimendan (LEVO) an inodilator indicated for the treatment of heart failure exerts multifaceted cardioprotective effects. Case-studies indicate protection against doxorubicin (DXR)-induced cardiotoxicity, but this effect remains elusive. We have previously shown that LEVO exerts cardioprotection against DXR-induced cardiomyopathy in a rat in vivo model, in a PKA/PKG-dependent manner. Purpose We sought to elucidate the mechanism of LEVO's induced cardioprotection and clarify the contribution of PKG and PKA pathways converging onto phospholamban (PLN). Methods As previously observed, LEVO at a dose of 24μg/kg protects against DXR cardiotoxicity, with protein kinase B (Akt)/ endothelial nitric oxide synthase (eNOS) and protein kinase A and G (PKA/PKG) pathways emerging as the main contributors to cardioprotection. Moreover, phospholamban seems to be the end-target of the signaling cascade. To verify the contribution of phospholamban, phospholamban deficient mice (PLN−/−) were assigned to PLN−/−/DXR (18mg/kg) and PLN−/−/DXR+LEVO (acute) (LEVO bolus, 24 μg/kg) groups for 14 days. Echocardiographic analysis was conducted in all groups and protocols. Furthermore, in order to solidify the mechanism of LEVO-mediated cardioprotection, primary adult ventricular murine cardiomyocytes (AVMCs) were isolated and treated with doxorubicin or/and LEVO as well with L-NAME, DT-2 and H-89 (eNOS, PKG and PKA inhibitors, respectively) and cardiomyocyte-toxicity was assessed. Results In the transgenic PLN−/− mice, LEVO did not exert cardioprotection, whilst the co-administration of doxorubicin and levosimendan led to an impaired Left ventricular function [FS (%): PLN−/−/Control: 39.01±0.42 vs PLN−/−/DXR: 38.12±0.51 in (NS); PLN−/−/DXR+LEVO: 35.38±0.86 (**p<0.01 vs PLN−/−/Control, *p<0.05 vs PLN−/−/DXR]. The latter data suggest that phospholamban is crucial for LEVO's cardioprotective effect. Finally, by investigating the contribution of different molecular pathways -shown to be induced by LEVO in vivo- on the AVMCs, we found that only PKA inhibition by H-89, abrogated LEVO-mediated cytoprotection, indicating that the effect is cAMP-PKA dependent. Conclusions Single-dose LEVO prevented DXR cardiotoxicity through a cAMP-PKA-phospholamban pathway, highlighting the role of inotropy in DXR cardiotoxicity. These preclinical data can stand as promising grounds for further clinical investigations.

scholarly journals Loss of UCHL1 rescues the defects related to Parkinson’s disease by suppressing glycolysis

2021 ◽  
Vol 7 (28) ◽  
pp. eabg4574
Author(s):  
Su Jin Ham ◽  
Daewon Lee ◽  
Wen Jun Xu ◽  
Eunjoo Cho ◽  
Sekyu Choi ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protein Kinase ◽  
Pyruvate Kinase ◽  
Mammalian Cells ◽  
Loss Of Function ◽  
Tripartite Motif ◽  
Carboxyl Terminal ◽  
Amp Activated Protein Kinase

The role of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1; also called PARK5) in the pathogenesis of Parkinson’s disease (PD) has been controversial. Here, we find that the loss of UCHL1 destabilizes pyruvate kinase (PKM) and mitigates the PD-related phenotypes induced by PTEN-induced kinase 1 (PINK1) or Parkin loss-of-function mutations in Drosophila and mammalian cells. In UCHL1 knockout cells, cellular pyruvate production and ATP levels are diminished, and the activity of AMP–activated protein kinase (AMPK) is highly induced. Consequently, the activated AMPK promotes the mitophagy mediated by Unc-51–like kinase 1 (ULK1) and FUN14 domain–containing 1 (FUNDC1), which underlies the effects of UCHL1 deficiency in rescuing PD-related defects. Furthermore, we identify tripartite motif–containing 63 (TRIM63) as a previously unknown E3 ligase of PKM and demonstrate its antagonistic interaction with UCHL1 to regulate PD-related pathologies. These results suggest that UCHL1 is an integrative factor for connecting glycolysis and PD pathology.

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