Sex-Specific Clinical Characteristics and Long-Term Outcomes in Patients With Myocardial Infarction With Non-obstructive Coronary Arteries

Background: Sex differences in clinical profiles and prognosis after acute myocardial infarction have been addressed for decades. However, the sex-based disparities among patients with myocardial infarction with non-obstructive coronary arteries (MINOCA) remain largely unreported. Here, we investigated sex-specific characteristics and long-term outcomes in MINOCA population.Methods: A total of 1,179 MINOCA patients were enrolled, including 867 men and 312 women. The mean follow-up was 41.7 months. The primary endpoint was a composite of major adverse cardiovascular events (MACE), including all-cause death, non-fatal reinfarction, revascularization, non-fatal stroke, and hospitalization for unstable angina or heart failure. Baseline data and outcomes were compared. Kaplan-Meier curves and Cox regression analyses were used to identify association between sex and prognosis.Results: Female patients with MINOCA had more risk profiles with regard to older age and higher prevalence of hypertension and diabetes compared with men. The evidence-based medical treatment was similar in men and women. The incidence of MACE (men vs. women: 13.8 vs. 15.3%, p = 0.504) did not differ significantly between the sexes. The Kaplan-Meier analysis also indicated that women had a similar incidence of MACE compared to men (log rank p = 0.385). After multivariate adjustment, female sex was not associated with the risk of MACE in overall (adjusted hazard ratio 1.02, 95% confidence interval: 0.72–1.44, p = 0.916) and in subgroups of MINOCA patients.Conclusion: The long-term outcomes were similar for men and women presenting with MINOCA despite older age and more comorbidities in women. Future research should aim to improve in-hospital and post-discharge care for both sexes with MINOCA

The role of PTEN in chronic growth hormone-induced hepatic insulin resistance.

Chronic growth hormone (GH) therapy has been shown to cause insulin resistance, but the mechanism remains unknown. PTEN, a tumor suppressor gene, is a major negative regulator of insulin signaling. In this study, we explored the effect of chronic GH on insulin signaling in the context of PTEN function. Balb/c healthy mice were given recombinant human or bovine GH intraperitoneally for 3 weeks. We found that phosphorylation of Akt was significantly decreased in chronic GH group and the expression of PTEN was significantly increased. We further examined this effect in the streptozotocin-induced Type I diabetic mouse model, in which endogenous insulin secretion was disrupted. Insulin/PI3K/Akt signaling was impaired. However, different from the observation in healthy mice, the expression of PTEN did not increase. Similarly, PTEN expression did not significantly increase in chronic GH-treated mice with hypoinsulinemia induced by prolonged fasting. We conducted in-vitro experiments in HepG2 cells to validate our in-vivo findings. Long-term exposure to GH caused similar resistance of insulin/PI3K/Akt signaling in HepG2 cells; and over-expression of PTEN enhanced the impairment of insulin signaling. On the other hand, disabling the PTEN gene by transfecting the mutant PTEN construct C124S or siPTEN, disrupted the chronic GH induced insulin resistance. Our data demonstrate that PTEN plays an important role in chronic-GH-induced insulin resistance. These findings may have implication in other pathological insulin resistance

Integrin β5 subunit regulates hyperglycemia-induced vascular endothelial cell apoptosis through FoxO1-mediated macroautophagy

Abstract. Background:. Hyperglycemia frequently induces apoptosis in endothelial cells and ultimately contributes to microvascular dysfunction in patients with diabetes mellitus (DM). Previous research reported that the expression of integrins as well as their ligands was elevated in the diseased vessels of DM patients. However, the association between integrins and hyperglycemia-induced cell death is still unclear. This research was designed to investigate the role played by integrin subunit β5 (ITGB5) in hyperglycemia-induced endothelial cell apoptosis. Methods:. We used leptin receptor knockout (Lepr-KO) (db/db) mice as spontaneous diabetes animal model. Selective deletion of ITGB5 in endothelial cell was achieved by injecting vascular targeted adeno-associated virus via tail vein. Besides, we also applied small interfering RNA in vitro to study the mechanism of ITGB5 in regulating high glucose-induced cell apoptosis. Results:. ITGB5 and its ligand, fibronectin, were both upregulated after exposure to high glucose in vivo and in vitro. ITGB5 knockdown alleviated hyperglycemia-induced vascular endothelial cell apoptosis and microvascular rarefaction in vivo. In vitro analysis revealed that knockdown of either ITGB5 or fibronectin ameliorated high glucose-induced apoptosis in human umbilical vascular endothelial cells (HUVECs). In addition, knockdown of ITGB5 inhibited fibronectin-induced HUVEC apoptosis, which indicated that the fibronectin-ITGB5 interaction participated in high glucose-induced endothelial cell apoptosis. By using RNA-sequencing technology and bioinformatic analysis, we identified Forkhead Box Protein O1 (FoxO1) as an important downstream target regulated by ITGB5. Moreover, we demonstrated that the excessive macroautophagy induced by high glucose can contribute to HUVEC apoptosis, which was regulated by the ITGB5–FoxO1 axis. Conclusion:. The study revealed that high glucose-induced endothelial cell apoptosis was positively regulated by ITGB5, which suggested that ITGB5 could potentially be used to predict and treat DM-related vascular complications

The effect of prolonged GH exposure and PTEN on Akt activity in HepG2 cells.

<p>(A) HepG2 cells were pretreated with GH or 30 min or 4 hours and harvested after insulin stimulation for 10 min. (B) Cells were transfected with wild type PTEN or PTEN mutant C124S, and harvested after insulin stimulation for 10 min. Densitometry absorbance values were averaged after they had been normalized to Akt for equal loading.</p

The effect of chronic hGH treatment on mice with hypoinsulinemia induced by prolonged fasting.

<p>Mice were treated with daily hGH at 1 µg/g or saline for 3 weeks, and subjected to fasting in the last 3 days. (A) Fasting body weights were measured just before and after the completion of 3-week GH administration. (B) Plasma insulin levels were measured using ELISA Kit. (C) Hepatic Akt activity was examined using Western blotting. (D) Hepatic PTEN expression was examined using Western blotting. (E) Liver lysates were immunoprecipitated with antibody against the p85α subunit of PI3K and were blotted with antiserum specific, either for total tyrosine phosphorylation of p85, or for p85 phosphorylated at tyrosine 458 and tyrosine 508. The values in bar graphs were displayed means ± standard errors.</p

Chronic bGH treatment led to insulin resistance.

<p>Mice were treated with bGH at 1 µg/g (controls received saline) daily for 3 weeks. (A) Fasting body weights were measured just before and after the completion of 3-week GH administration. (B) Hepatic Akt activity was examined in mice challenged by insulin 10 minutes prior to sacrifice using Western blotting. (C) Hepatic Akt activity was examined in mice challenged by 10-min saline prior to sacrifice. (D) Liver lysates from mice challenged by 10-min insulin prior to sacrifice were immunoprecipitated with antibody against PTEN, and were blotted with the same antibody. (E) Hepatic PTEN expression was examined in mice challenged by 10-min saline prior to sacrifice. Liver lysates from mice challenged by 10-min insulin (F) or saline (G) prior to sacrifice were immunoprecipitated with antibody against the p85α subunit of PI3K and were blotted with antiserum specific, either for total tyrosine phosphorylation of p85, or for p85 phosphorylated at tyrosine 458 and tyrosine 508. The values in bar graphs were displayed as means ± standard errors.</p

Knockdown of PTEN gene disrupted chronic GH induced insulin resistance.

<p>Cells were transfected with siRNA targeted for PTEN (A), PTEN mutant C124S (B) or wtPTEN (C), and were stimulated with GH and Insulin as stated in Methods and materials. Densitometry absorbance values were averaged after they had been normalized to Akt for equal loading.</p

Chronic hGH treatment induced insulin resistance and enhanced the expression of PTEN.

<p>Mice were treated with daily hGH at 1 µg/g (controls received saline) for 3 weeks. (A) Fasting body weights were measured just before and after the completion of 3-week GH administration. (B) Plasma levels of Insulin were measured in mice without pre-sacrifice administration of insulin using ELISA Kit. (C) Hepatic Akt activity was examined in mice challenged by 10-minute insulin prior to sacrifice using Western blotting. (D) Hepatic Akt activity was examined in mice challenged by 10-min saline prior to sacrifice using Western blotting. (E) Hepatic PTEN expression was examined in mice challenged by 10-min insulin prior to sacrifice. (F) Hepatic PTEN expression was examined in mice challenged by 10-min saline prior to sacrifice. Liver lysates from mice challenged by 10-min insulin (G) or saline (H) prior to sacrifice were immunoprecipitated with antibody against the p85α subunit of PI3K and were blotted with antiserum specific, either for total tyrosine phosphorylation of p85, or for p85 phosphorylated at tyrosine 458 and tyrosine 508. The values in bar graphs were displayed as means ± standard errors.</p