Pioglitazone Induces Cardiomyocyte Apoptosis and Inhibits Cardiomyocyte Hypertrophy Via VEGFR-2 Signaling Pathway / Pioglitazona Induz Apoptose e Inibe Hipertrofia de Cardiomiócitos pela Via de Sinalização do VEGFR-2

Abstract Background: Pioglitazone has been widely used as an insulin-sensitizing agent for improving glycemic control in patients with type 2 diabetes mellitus. However, cardiovascular risk and protective effects of pioglitazone remain controversial. Objectives: In this study, we investigated whether pioglitazone affects cardiomyocyte apoptosis and hypertrophy by regulating the VEGFR-2 signaling pathway. Methods: Cardiomyocytes were enzymatically isolated from 1- to 3-day-old Sprague-Dawley rat ventricles. Effects of pioglitazone and the VEGFR-2-selective inhibitor apatinib on cardiomyocyte apoptotic rate was determined using flow cytometry, and hypertrophy was evaluated using [3H]-leucine incorporation. The protein expressions of unphosphorylated and phosphorylated VEGFR-2, Akt, P53, and mTOR were determined by Western-Blotting. Analysis of variance (ANOVA) was used to assess the differences between groups. Results: Pioglitazone and VEGFR-2-selective inhibitor apatinib reduced rat cardiomyocyte viability and cardiomyocyte hypertrophy induced by angiotensin II in vitro. Furthermore, in the same in vitro model, pioglitazone and apatinib significantly increased the expression of Bax and phosphorylated P53 and decreased the expression of phosphorylated VEGFR-2, Akt, and mTOR, which promote cardiomyocyte hypertrophy. Conclusions: These findings indicate that pioglitazone induces cardiomyocyte apoptosis and inhibits cardiomyocyte hypertrophy by modulating the VEGFR-2 signaling pathway.

Resumo Fundamento: A pioglitazona tem sido amplamente utilizada como droga sensibilizadora da insulina para melhorar o controle glicêmico em pacientes com diabetes mellitus tipo 2. No entanto, o risco cardiovascular bem como os efeitos protetores da pioglitazona ainda são controversos. Objetivos: Neste estudo, investigamos se os efeitos da pioglitazona sobre a apoptose e a hipertrofia de cardiomiócitos ocorrem via regulação da via de sinalização do VEGFR-2. Métodos: os cardiomiócitos foram isolados enzimaticamente dos ventrículos de ratos Sprague-Dawley de 1-3 anos de vida. Os efeitos da pioglitazona e do inibidor seletivo de VEGFR-2 apatinib sobre a taxa de apoptose dos cardiomiócitos foram avaliados por citometria de fluxo, e a hipertrofia avaliada por incorporação de leucina-[3H]. As expressões de VEGFR-2, Akt, P53, e mTOR fosforiladas e não fosforiladas foram determinadas por Western Blotting. Análise de variância (ANOVA) foi usada para avaliar diferenças entre os grupos. Resultados: a pioglitazona e o apatinib reduziram a viabilidade e a hipertrofia de cardiomiócitos induzida por angiotensina II in vitro. Além disso, no mesmo modelo in vitro, a pioglitazona e o apatinib aumentaram significativamente a expressão de Bax e P53 fosforilada, e diminuiu a expressão de VEGFR-2, Akt, e mTOR, que promove hipertrofia de cardiomiócitos. Conclusões: Esses resultados indicam que a pioglitazona induz a apoptose e inibe a hipertrofia de cardiomiócitos pela modulação da via de sinalização de VEGFR-2.

Pioglitazone Induces Cardiomyocyte Apoptosis and Inhibits Cardiomyocyte Hypertrophy Via VEGFR-2 Signaling Pathway.

BACKGROUND: Pioglitazone has been widely used as an insulin-sensitizing agent for improving glycemic control in patients with type 2 diabetes mellitus. However, cardiovascular risk and protective effects of pioglitazone remain controversial. OBJECTIVES: In this study, we investigated whether pioglitazone affects cardiomyocyte apoptosis and hypertrophy by regulating the VEGFR-2 signaling pathway. METHODS: Cardiomyocytes were enzymatically isolated from 1- to 3-day-old Sprague-Dawley rat ventricles. Effects of pioglitazone and the VEGFR-2-selective inhibitor apatinib on cardiomyocyte apoptotic rate was determined using flow cytometry, and hypertrophy was evaluated using [3H]-leucine incorporation. The protein expressions of unphosphorylated and phosphorylated VEGFR-2, Akt, P53, and mTOR were determined by Western-Blotting. Analysis of variance (ANOVA) was used to assess the differences between groups. RESULTS: Pioglitazone and VEGFR-2-selective inhibitor apatinib reduced rat cardiomyocyte viability and cardiomyocyte hypertrophy induced by angiotensin II in vitro. Furthermore, in the same in vitro model, pioglitazone and apatinib significantly increased the expression of Bax and phosphorylated P53 and decreased the expression of phosphorylated VEGFR-2, Akt, and mTOR, which promote cardiomyocyte hypertrophy. CONCLUSIONS: These findings indicate that pioglitazone induces cardiomyocyte apoptosis and inhibits cardiomyocyte hypertrophy by modulating the VEGFR-2 signaling pathway.

5-Year Safety and Efficacy of Resolute Zotarolimus-Eluting Stent: The RESOLUTE Global Clinical Trial Program.

OBJECTIVES: The authors evaluated the 5-year cumulative incidence of cardiovascular events following Resolute zotarolimus-eluting stent (R-ZES) implantation. BACKGROUND: Individual trials are often underpowered to show differences for low-frequency adverse events. The R-ZES was studied in 10 prospective clinical trials, designed with identical adverse event definitions, ascertainment, and adjudication. METHODS: The RESOLUTE Global Clinical Trial Program includes 7,618 patients treated with R-ZES: RESOLUTE first-in-human study (N = 139), RESOLUTE All Comers (N = 1,140), RESOLUTE International (N = 2,349), RESOLUTE US (N = 1,402), RESOLUTE US 38 mm (N = 114), RESOLUTE Japan (N = 100), RESOLUTE Japan Small Vessel Study (N = 65), RESOLUTE Asia (N = 311), RESOLUTE China Randomized Controlled Trial (N = 198), and RESOLUTE China Registry (N = 1,800). The 5-year cumulative incidence of events was calculated. RESULTS: The 5-year cumulative incidence of cardiac events was 13.4% for target lesion failure and included 5.0% cardiac death, 4.4% target vessel myocardial infarction, and 6.3% clinically driven target lesion revascularization. Dual-antiplatelet therapy at 1, 3, and 5 years was 91%, 37%, and 32%, respectively. The 5-year cumulative incidence of definite or probable stent thrombosis was 1.2%, which comprised 0.7% at 1 year and an annualized rate of 0.1% thereafter. Five-year use of dual-antiplatelet therapy varied geographically from 63% in Japan to 11% in Europe. CONCLUSIONS: In the largest group of R-ZES patients examined to date, the majority of stent-related events, including target vessel myocardial infarction and stent thrombosis, occurred within the first year of implantation with much lower risks of these events out to 5 years.