MicroRNAs (miRs) regulate a number of physiological and pathological processes, including myocardial chronic hypoxia. Previous studies revealed that the expression of miR-146b is increased in vitro and in vivo following the induction of hypoxia. In the present study, the role of miR‑146b in hypoxic cardiomyocytes, and the mechanisms underlying its activity, were investigated. The expression of miR‑146b was measured in tissue samples from patients with congenital heart disease by reverse transcription‑quantitative polymerase chain reaction. The rat H9c2 cardiomyocyte cell line was transfected with an miR‑146b inhibitor or the experimental controls, and the cells were maintained under hypoxic conditions for 72 h. The expression of miR‑146b increased following the induction of hypoxia. Transfection with the miR‑146b inhibitor enhanced the release of lactate dehydrogenase and increased hypoxia‑induced apoptosis, as determined by terminal deoxynucleotidyl transferase dUTP nick‑end labeling, Hoechst 33258 staining, JC‑1 assay (measuring mitochondrial membrane permeability) and annexin V/propidium iodide analysis. A decreased expression of Bcl‑2 was observed, whereas the expression levels of cleaved‑caspase 3 and Bax were increased. Western blot analysis and a dual luciferase reporter assay confirmed that ribonuclease L is a direct target of miR‑146b. Furthermore, inhibition of miR-146b increased the activation of nuclear factor-κB and signal transducer and activator of transcription 3. In conclusion, the inhibition of miR‑146b may increase hypoxia-induced cardiomyocyte apoptosis.
Background The sodium‐glucose cotransporter 2 inhibitor canagliflozin reduced the risk of first cardiovascular composite events in the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial. In this post hoc analysis, we evaluated the effect of canagliflozin on total (first and recurrent) cardiovascular events. Methods and Results The CREDENCE trial compared canagliflozin or matching placebo in 4401 patients with type 2 diabetes, albuminuria, and estimated glomerular filtration rate of 30 to <90 mL/min per 1.73 m 2 , over a median of 2.6 years. The primary outcome was analyzed as a composite of any cardiovascular event including myocardial infarction, stroke, hospitalization for heart failure, hospitalization for unstable angina, and cardiovascular death. Negative binomial regression models were used to assess the effect of canagliflozin on the net burden of cardiovascular events. During the trial, 634 patients had 883 cardiovascular events, of whom 472 (74%) had just 1 cardiovascular event and 162 (26%) had multiple cardiovascular events. Canagliflozin reduced first cardiovascular events by 26% (hazard ratio, 0.74 [95% CI, 0.63–0.86]; P <0.001) and total cardiovascular events by 29% (incidence rate ratio, 0.71 [95% CI, 0.59–0.86]; P <0.001). The absolute risk difference per 1000 patients treated over 2.5 years was −44 (95% CI, −67 to −21) first cardiovascular events and −73 (95% CI, −114 to −33) total events. Conclusions Canagliflozin reduced cardiovascular events, with a larger absolute benefit for total cardiovascular than first cardiovascular events. These findings provide further support for the benefit of continuing canagliflozin therapy after an initial event to prevent recurrent cardiovascular events. Registration Information URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT02065791.
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