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Sildenafil augments early protective transcriptional changes after ischemia in mouse myocardium.

ABSTRACT: Recently, targeting cyclic-GMP specific phosphodiesterase-5 (PDE5) has attracted much interest in several cardiopulmonary diseases, in particular myocardial ischemia (MI). Although multiple mechanisms were postulated for these beneficial effects at cellular level, early transcriptional changes were unknown. The aim of present study was to examine gene expression profiles in response to MI after 24 h of ischemia in murine model and compare transcriptional modulation by sildenafil, a popular phosphodiesterase 5 (PDE5) inhibitor. Mice were divided into four groups: Control sham (C), Sildenafil sham (S), Control MI (CMI) and Sildenafil MI (SMI). Sildenafil was given at a dose of 0.7 mg/kg intraperitoneally 30 min before LAD occlusion. cDNA microarray analysis of peri-infarct tissue was done using a custom cloneset and employing a looped dye swap design. Replicate signals were median averaged and normalized using LOWESS algorithm. R/MAANOVA analysis was used and false discovery rate corrected permutation p-values <0.005 were employed as significance thresholds. 156 genes were identified as significantly regulated demonstrating fold difference >1.5 in at least one of the four groups. 52 genes were significantly upregulated in SMI compared to CMI. For a randomly chosen subset of genes (9), microarray data were confirmed through real time RT-PCR. The differentially expressed genes could be classified into following groups based on their function: phosphorylation/dephosphorylation, apoptosis, differentiation, ATP binding. Our results suggest that sildenafil treatment might regulate early genetic reprogramming strategy for preservation of the ischemic myocardium.

SUBMITTER: Vidavalur R

PROVIDER: S-EPMC2650511 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Sildenafil augments early protective transcriptional changes after ischemia in mouse myocardium.

Vidavalur Ramesh R Penumathsa Suresh Varma SV Thirunavukkarasu Mahesh M Zhan Lijun L Krueger Winfried W Maulik Nilanjana N

Gene 20081025 1-2

Recently, targeting cyclic-GMP specific phosphodiesterase-5 (PDE5) has attracted much interest in several cardiopulmonary diseases, in particular myocardial ischemia (MI). Although multiple mechanisms were postulated for these beneficial effects at cellular level, early transcriptional changes were unknown. The aim of present study was to examine gene expression profiles in response to MI after 24 h of ischemia in murine model and compare transcriptional modulation by sildenafil, a popular phosp ...[more]

PMID: 19013509

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Project description:Regorafenib is approved for the treatment of colorectal cancer and hepatocellular carcinoma. In the trial NCT02466802, we have discovered that regorafenib can be safely combined with the phosphodiesterase 5 inhibitor sildenafil in advanced solid tumor patients. The present studies determined whether the approved ERBB1/2/4 and RAS downregulating drug neratinib, could enhance the lethality of [regorafenib + sildenafil]. Neratinib enhanced [regorafenib + sildenafil] lethality in a greater than additive fashion in colon cancer cells. The drug combination reduced the expression of mutant K-RAS and of multiple histone deacetylase (HDAC) proteins that required autophagosome formation. It caused green fluorescent protein or red fluorescent protein-tagged forms of K-RAS V12 to localize into large intracellular vesicles. Compared with [regorafenib + sildenafil], the three-drug combination caused greater and more prolonged activation of the ATM-AMPK-ULK-1 pathway and caused a greater suppression and prolonged inactivation of mammalian target of rapamycin, AKT, and p70 S6K. Approximately 70% of enhanced lethality caused by neratinib required ataxia-telangiectasia-mutated (ATM)-AMP-dependent protein kinase (AMPK) signaling whereas knockdown of Beclin1, ATG5, FADD, and CD95 completely prevented the elevated killing effect. Exposure of cells to [regorafenib + sildenafil] reduced the expression of the checkpoint immunotherapy biomarkers programmed death-ligand 1, ornithine decarboxylase, and indoleamine 2,3-dioxygenase-1 and increased the expression of major histocompatibility complex A (MHCA), which also required autophagosome formation. Knockdown of specific HDAC proteins recapitulated the effects observed using chemical agents. In vivo, using mouse cancer models, neratinib significantly enhanced the antitumor efficacy of [regorafenib + sildenafil]. Our data support performing a new three drug Phase I trial combining regorafenib, sildenafil, and neratinib.

Project description:BackgroundSevoflurane postconditioning (SevP) effectively relieves myocardial ischemia/reperfusion (I/R) injury but performs poorly in the diabetic myocardium. Previous studies have revealed the important role of increased oxidative stress in diabetic tissues. Notably, mitochondrial fission mediated by dynamin-related protein 1 (Drp1) is an upstream pathway of reactive oxygen production. Whether the ineffectiveness of SevP in the diabetic myocardium is related to Drp1-dependent mitochondrial fission remains unknown. This study aimed to explore the important role of Drp1 in the diabetic myocardium and investigate whether Drp1 inhibition could restore the cardioprotective effect of SevP.MethodsIn the first part of the study, adult male Sprague-Dawley rats were divided into 6 groups. Rats in the diabetic groups were fed with high-fat and high-sugar diets for 8 weeks and injected intraperitoneally with streptozotocin (35 mg/kg). Myocardial I/R was induced by 30 min of occlusion of the left anterior descending branch of the coronary artery followed by 120 min of reperfusion. SevP was applied by continuous inhalation of 2.5 % sevoflurane 1 min before reperfusion, which lasted for 10 min. In the second part of the study, we applied mdivi-1 to investigate whether Drp1 inhibition could restore the cardioprotective effect of SevP in the diabetic myocardium. The myocardial infarct size, mitochondrial ultrastructure, apoptosis index, SOD activity, MDA content, and Drp1 expression were detected.ResultsTTC staining and TUNEL results showed that the myocardial infarct size and apoptosis index were increased in the diabetic myocardium. However, SevP significantly alleviated myocardial I/R injury in the normal myocardium but not in the diabetic myocardium. Additionally, we found an elevation in Drp1 expression, accompanied by more severe fission-induced structural damage and oxidative stress in the diabetic myocardium. Interestingly, we discovered that the beneficial effect of SevP was restored by mdivi-1, which significantly suppressed mitochondrial fission and oxidative stress.ConclusionsOur study demonstrates the crucial role of mitochondrial fission dependent on Drp1 in the diabetic myocardium subjected to I/R, and strongly indicates that Drp1 inhibition may restore the cardioprotective effect of SevP in diabetic rats.

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Sildenafil augments early protective transcriptional changes after ischemia in mouse myocardium.

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Sildenafil augments early protective transcriptional changes after ischemia in mouse myocardium.

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