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The cardiotoxicity of adriamycin limits its clinical use as a powerful drug for solid tumors and malignant hematological disease. Although the precise mechanism by which it causes cardiac damage is not yet known, it has been suggested that apoptosis is the principal process in adriamycin-induced cardiomyopathy, which involves DNA fragmentation, cytochrome C release, and caspase activation. However, there has been no direct evidence for the critical involvement of caspase-3 in adriamycin-induced apoptosis. To determine the requirements for the activation of caspase-3 in adriamycin-treated cardiac cells, the effect of a caspase inhibitor on the survival of and apoptotic changes in H9c2 cells was examined. Exposure of H9c2 cells to adriamycin resulted in a time- and dose-dependent cell death, and the cleavage of pro-caspase-3 and of the nuclear protein poly (ADP'ribose) polymerase (PARP). However, neither the reduction of cell viability nor the characteristic morphological changes induced by adriamycin were prevented by pretreatment with the general caspase inhibitor z-VAD.FMK. In contrast, caspase inhibition effectively blocked the apoptosis induced by H202 in H9c2 cells, as determined by an MTT assay or microscopy. We also observed that p53 expression was increased by adriamycin, and this increase was not affected by the inhibition of caspase activity, suggesting a role for p53 in adriamycin-induced caspase-independent apoptosis in cardiac toxicity.

An AU-rich element (ARE) in the 3-untranslated region (UTR) of bcl-2 mRNA has previously been shown to be responsible for destabilizing bcl-2 mRNA during apoptosis through increasing AUF1 binding. In the present study, we investigated the effect of the region upstream of the ARE on bcl-2 mRNA stability using serial deletion constructs of the 3-UTR of bcl-2. Deletion of 30 nucleotides mostly consisting of the CA repeats, located upstream of the ARE, resulted in the stabilization of bcl-2 mRNA abundance, in the absence or presence of the ARE. The specificity of the CA repeats in terms of destabilizing bcl-2 mRNA was proven by the substituting the CA repeats with other alternative repeats of purine/ pyriminine, but this had no effect on the stability of bcl-2 mRNA. CA repeats alone, however, failed to confer instability to bcl-2 or gfp reporter mRNAs, indicating a requirement for additional sequences in the upstream region of the 3-UTR. Serial deletion and replacement of a part of the region upstream of the CA repeats revealed that the entire 131-nucleotide upstream region is an essential prerequisite for the CA repeat-dependent destabilization of bcl-2 mRNA. Unlike the ARE, CA repeatmediated degradation of bcl-2 mRNA was not accelerated upon apoptotic stimulus. Moreover, the upstream sequences and CA repeats are conserved among mammals. Collectively, CA repeats contribute to the constitutive decay of bcl-2 mRNA in the steady states, thereby maintaining appropriate bcl-2 levels in mammalian cells.Apoptosis is a tightly controlled cellular suicide program that is critical for the successful development of multicellular organisms, the maintenance of normal tissue homeostasis, and removal of damaged cells (1). The protooncogene bcl-2, originally isolated from the chromosomal breakpoint of a t(14, 18)-bearing B cell lymphoma, serves as an important repressor of apoptosis in a variety of cell types (2, 3). In line with its significant role in altering susceptibility to apoptosis, investigations of the mechanisms by which bcl-2 expression is modulated may prove crucial for identifying therapeutic strategies for cancer and some neurodegenerative diseases and for defining the role of bcl-2 in the development of multiple tissues (4).Recent studies have indicated that bcl-2 is regulated at both the transcriptional and posttranscriptional levels. A number of negative transcriptional regulatory sites have been described in the bcl-2 promoter region (5, 6), and several transcription factors, including cAMP response element binding protein, AMyb and WT1, are known to be involved in the positive regulation of bcl-2 transcription (7-9). In addition to the promoter region, some sequences within the coding region, such as estrogen response elements, have also been demonstrated to mediate the transcriptional modulation of bcl-2, as was shown in breast cancer cell lines (10). The posttranscriptional modification of bcl-2 includes the phosphorylation of Bcl-2 at the putative mitogen-activated protein kinase sites, which confers resista...

Background: In patients with acute coronary syndrome (ACS) with a high risk of ischemia, the impact of ticagrelor monotherapy after short-term dual antiplatelet therapy (DAPT) has not been clearly elucidated. Methods: This post hoc analysis of the TICO trial (Ticagrelor Monotherapy After 3 Months in the Patients Treated With New Generation Sirolimus-Eluting Stent for Acute Coronary Syndrome) compared the impact of ticagrelor monotherapy after 3-month DAPT versus ticagrelor-based 12-month DAPT in patients with high-ischemic risk ACS, defined as any of the following: number of stents implanted ≥3, total stent length >60 mm, complex procedures (chronic total occlusion, left main occlusion, or bifurcation plaques remedied using the 2-stent technique), or a history of diabetes or chronic kidney disease. Ischemic (composite of death, myocardial infarction, stent thrombosis, stroke, and target vessel revascularization) and bleeding outcomes (major bleeding) were evaluated at 12 months. Results: Of the total population (N=3056), 1473 (48.2%) patients were identified as having high-ischemic risk ACS. The rate of the ischemic outcome was significantly higher in high-ischemic risk ACS patients than in nonhigh-ischemic risk ACS patients (3.9% versus 1.9%, hazard ratio, 2.14 [95% CI, 1.37–3.35], P =0.001). Furthermore, the risk of major bleeding (3.2% versus 1.5%, hazard ratio, 2.23 [95% CI, 1.36–3.68], P =0.001) and the composite ischemic and bleeding outcome (6.6% versus 3.3%, hazard ratio, 2.02 [95% CI, 1.44–2.84], P <0.001) were also higher in the high-risk ACS population. In ACS patients with or without high-ischemic risk, the effect of ticagrelor monotherapy after 3-month DAPT, as compared to that of 12-month DAPT, was consistent with ischemic ( P int =0.718), bleeding ( P int =0.092), and composite outcomes ( P int =0.094) without significant interactions. Conclusions: There were no significant heterogeneities in the impact of ticagrelor monotherapy after 3-month DAPT compared with that of ticagrelor-based 12-month DAPT on clinical outcomes according to the presence of high-ischemic risk. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02494895.

ImportanceIn patients with coronary artery disease, some guidelines recommend initial statin treatment with high-intensity statins to achieve at least a 50% reduction in low-density lipoprotein cholesterol (LDL-C). An alternative approach is to begin with moderate-intensity statins and titrate to a specific LDL-C goal. These alternatives have not been compared head-to-head in a clinical trial involving patients with known coronary artery disease.ObjectiveTo assess whether a treat-to-target strategy is noninferior to a strategy of high-intensity statins for long-term clinical outcomes in patients with coronary artery disease.Design, Setting, and ParticipantsA randomized, multicenter, noninferiority trial in patients with a coronary disease diagnosis treated at 12 centers in South Korea (enrollment: September 9, 2016, through November 27, 2019; final follow-up: October 26, 2022).InterventionsPatients were randomly assigned to receive either the LDL-C target strategy, with an LDL-C level between 50 and 70 mg/dL as the target, or high-intensity statin treatment, which consisted of rosuvastatin, 20 mg, or atorvastatin, 40 mg.Main Outcomes and MeasuresPrimary end point was a 3-year composite of death, myocardial infarction, stroke, or coronary revascularization with a noninferiority margin of 3.0 percentage points.ResultsAmong 4400 patients, 4341 patients (98.7%) completed the trial (mean [SD] age, 65.1 [9.9] years; 1228 females [27.9%]). In the treat-to-target group (n = 2200), which had 6449 person-years of follow-up, moderate-intensity and high-intensity dosing were used in 43% and 54%, respectively. The mean (SD) LDL-C level for 3 years was 69.1 (17.8) mg/dL in the treat-to-target group and 68.4 (20.1) mg/dL in the high-intensity statin group (n = 2200) (P = .21, compared with the treat-to-target group). The primary end point occurred in 177 patients (8.1%) in the treat-to-target group and 190 patients (8.7%) in the high-intensity statin group (absolute difference, –0.6 percentage points [upper boundary of the 1-sided 97.5% CI, 1.1 percentage points]; P &amp;lt; .001 for noninferiority).Conclusions and RelevanceAmong patients with coronary artery disease, a treat-to-target LDL-C strategy of 50 to 70 mg/dL as the goal was noninferior to a high-intensity statin therapy for the 3-year composite of death, myocardial infarction, stroke, or coronary revascularization. These findings provide additional evidence supporting the suitability of a treat-to-target strategy that may allow a tailored approach with consideration for individual variability in drug response to statin therapy.Trial RegistrationClinicalTrials.gov Identifier: NCT02579499

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Background: Although stent underexpansion on intravascular ultrasound (IVUS) has been a major predictor for adverse outcomes in previous studies, these studies have primarily focused on angiographic restenosis or repeat revascularization with short-term follow-up. This study sought to evaluate the long-term benefit of different criteria for IVUS-defined optimal stent expansion on hard clinical outcomes. Methods: From the pooled data of 2 randomized trials, IVUS-XPL (Impact of Intravascular Ultrasound Guidance on the Outcomes of Xience Prime Stents in Long Lesions) and ULTIMATE (Intravascular Ultrasound Guided Drug Eluting Stents Implantation in All-Comers Coronary Lesions) that compared IVUS- versus angiography-guided drug-eluting stent implantation, a total of 1254 patients with IVUS-guided drug-eluting stent implantation into 1484 long lesions (implanted stent length, ≥28 mm) were included. Different criteria for IVUS-defined optimal stent expansion based on minimum stent area (MSA) as an absolute measure or MSA relative to reference lumen area were applied and validated. The primary end point was composite of cardiac death, target lesion–related myocardial infarction, or stent thrombosis at 3 years. Results: The rate of the primary end point was lower in patients with optimal stent expansion versus those without optimal stent expansion according to 3 IVUS-defined optimal stent expansion criteria: MSA >5.5 mm 2 (0.5% versus 2.2%; hazard ratio, 0.21 [95% CI, 0.06–0.75]; P =0.008), MSA >5.0 mm 2 (0.6% versus 2.6%; hazard ratio, 0.24 [95% CI, 0.09–0.68]; P =0.003), and MSA/distal reference lumen area >90% (0.5% versus 2.4%; hazard ratio, 0.32 [95% CI, 0.12–0.88]; P =0.019). Achieving other relative expansion criteria, MSA/distal reference lumen area >100% or 80% or MSA/average reference lumen area >90% or 80%, was not associated with a reduction in hard clinical events. Conclusions: In patients undergoing IVUS-guided drug-eluting stent implantation for long lesions, achieving optimal stent expansion of MSA >5.5 mm 2 , >5.0 mm 2 , or MSA/distal reference lumen area >90% was associated with improved long-term hard clinical outcomes.