Datasheet1_SGLT2 inhibition, plasma proteins, and heart failure: a proteome-wide Mendelian Randomization and colocalization study.docx

ObjectiveTo investigate the causal contributions of Sodium-glucose cotransporter 2 (SGLT2) inhibition on Heart Failure (HF) and identify the circulating proteins that mediate SGLT2 inhibition's effects on HF.MethodsApplying a two-sample, two-step Mendelian Randomization (MR) analysis, we aimed to estimate: (1) the causal impact of SGLT2 inhibition on HF; (2) the causal correlation of SGLT2 inhibition on 4,907 circulating proteins; (3) the causal association of SGLT2 inhibition-driven plasma proteins on HF. Genetic variants linked to SGLT2 inhibition derived from the previous studies. The 4,907 circulating proteins were derived from the deCODE study. Genetic links to HF were obtained through the Heart Failure Molecular Epidemiology for Therapeutic Targets (HERMES) consortium.ResultsSGLT2 inhibition demonstrated a lower risk of HF (odds ratio [OR] = 0.44, 95% CI [0.26, 0.76], P = 0.003). Among 4,907 circulating proteins, we identified leucine rich repeat transmembrane protein 2 (LRRTM2), which was related to both SGLT2 inhibition and HF. Mediation analysis revealed that the impact of SGLT2 inhibition on HF operates indirectly through LRRTM2 [β = −0.20, 95% CI (−0.39, −0.06), P = 0.02] with a mediation proportion of 24.6%. Colocalization analysis provided support for the connections between LRRTM2 and HF.ConclusionThe study indicated a causative link between SGLT2 inhibition and HF, with plasma LRRTM2 potentially serving as a mediator.</p

Table1_SGLT2 inhibition, plasma proteins, and heart failure: a proteome-wide Mendelian Randomization and colocalization study.xlsx

ObjectiveTo investigate the causal contributions of Sodium-glucose cotransporter 2 (SGLT2) inhibition on Heart Failure (HF) and identify the circulating proteins that mediate SGLT2 inhibition's effects on HF.MethodsApplying a two-sample, two-step Mendelian Randomization (MR) analysis, we aimed to estimate: (1) the causal impact of SGLT2 inhibition on HF; (2) the causal correlation of SGLT2 inhibition on 4,907 circulating proteins; (3) the causal association of SGLT2 inhibition-driven plasma proteins on HF. Genetic variants linked to SGLT2 inhibition derived from the previous studies. The 4,907 circulating proteins were derived from the deCODE study. Genetic links to HF were obtained through the Heart Failure Molecular Epidemiology for Therapeutic Targets (HERMES) consortium.ResultsSGLT2 inhibition demonstrated a lower risk of HF (odds ratio [OR] = 0.44, 95% CI [0.26, 0.76], P = 0.003). Among 4,907 circulating proteins, we identified leucine rich repeat transmembrane protein 2 (LRRTM2), which was related to both SGLT2 inhibition and HF. Mediation analysis revealed that the impact of SGLT2 inhibition on HF operates indirectly through LRRTM2 [β = −0.20, 95% CI (−0.39, −0.06), P = 0.02] with a mediation proportion of 24.6%. Colocalization analysis provided support for the connections between LRRTM2 and HF.ConclusionThe study indicated a causative link between SGLT2 inhibition and HF, with plasma LRRTM2 potentially serving as a mediator.</p

Controllable Fabrication of Poly(Arylene Ether Nitrile) Dielectrics for Thermal-Resistant Film Capacitors

High-temperature-resistant dielectric films, the heart of energy storage components in film capacitors, are key elements to ensure that the capacitors operate properly in harsh environments. Herein, a kind of flexible thermal-resistant poly­(arylene ether nitrile) (TR-PEN) dielectric film with controllable high-temperature resistance is fabricated through post self-crosslinking of PEN at different temperatures for different times. The dielectric films can present extremely high thermal stability (Tg > 370 °C), a long service life at 300 °C (4.5 × 104 min, 95 wt % of the residual weight), and a low temperature coefficient of dielectric constant from 50 to 300 °C (–4 °C–1). The retention of the energy density of TR-PEN350 at 300 °C is higher than 80% compared with that at room temperature. These results indicate that the TR-PEN films can be used over a long term as capacitor films at temperatures up to 300 °C. Besides, the simple and controllable fabrication technique for the TR-PEN can be easily industrialized

Low dose of H₂O₂ induced senescence in H9C2 cells without causing apoptosis.

<p>A, Representative pictures of sa-gal-stained H9C2 cells. Left, control (without H₂O₂); right, 3 days after stimulation with 30 µmol/L of H₂O₂ for 2 hours. B, Number of sa-gal–positive cells per microscopic field 3 days after a 2-hour H₂O₂ (0–100 µmol/L) treatment. Bars represent means±SEM (*<i>P</i><0.05 vs control; n = 3 experiments). C, Caspase-3 activity, measured as luminescence, in H9C2 3 days after treatment with H₂O₂ (0–200 µmol/L) for 2 hours. Bars represent means±SEM (*<i>P</i><0.05 vs control; n = 3 experiments).</p

Effects of BK on SOD expression and activity in H9C2 cells treated with H₂O₂.

<p>A, Effects of HOE-140 on the beneficial effects of BK on SOD expression in H9C2 cells treated with H₂O₂. B, Effects of L-NAME on the beneficial effects of BK on SOD expression in H9C2 cells treated with H₂O₂. C, Effects of HOE-140 and L-NAME on the beneficial effects of BK on total SOD (T-SOD) activity in H9C2 cells treated with H₂O₂. Bars represent means ±SEM (*<i>P</i><0.05 vs control; ^#<i>P</i><0.05 vs H₂O₂; ^&<i>P</i><0.05 vs H₂O₂+BK; n = 3 experiments).</p

Effects of BK on membrane p47, p67 and gp91 expression and NADPH oxidase activity in H9C2 cells treated with H₂O₂.

<p>A, Effects of BK on membrane p47, p67 and gp91 expression in H9C2 cells treated with H₂O₂ and HOE-140. B, Effects of BK on membrane p47, p67 and gp91 expression in H9C2 cells treated with H₂O₂ and L-NAME. C, Effects of BK on NADPH oxidase activity in H9C2 cells treated with H₂O₂. Bars represent means ±SEM (*<i>P</i><0.05 vs control; ^#<i>P</i><0.05 vs H₂O₂; ^&<i>P</i><0.05 vs H₂O₂+BK; n = 3 experiments).</p

Effects of BK on ROS production in H9C2 cells treated with H₂O₂.

<p>A, ROS generation was measured by the DCF fluorescence intensity. B, Superoxide generation was measured by the commercial available kit. Bars represent means ±SEM (*<i>P</i><0.05 vs control; ^#<i>P</i><0.05 vs H₂O₂; ^&<i>P</i><0.05 vs H₂O₂+BK; n = 6).</p

Bradykinin Inhibits Oxidative Stress-Induced Cardiomyocytes Senescence via Regulating Redox State

<div><p>Background</p><p>Cell senescence is central to a large body of age related pathology, and accordingly, cardiomyocytes senescence is involved in many age related cardiovascular diseases. In consideration of that, delaying cardiomyocytes senescence is of great importance to control clinical cardiovascular diseases. Previous study indicated that bradykinin (BK) protected endothelial cells from senescence induced by oxidative stress. However, the effects of bradykinin on cardiomyocytes senescence remain to be elucidated. In this study, we investigated the effect of bradykinin on H₂O₂-induced H9C2 cells senescence.</p><p>Methods and Results</p><p>Bradykinin pretreatment decreased the senescence induced by H₂O₂ in cultured H9C2 cells in a dose dependent manner. Interestingly, 1 nmol/L of BK almost completely inhibited the increase in senescent cell number and p21 expression induced by H₂O₂. Since H₂O₂ induces senescence through superoxide-induced DNA damage, we also observed the DNA damage by comet assay, and BK markedly reduced DNA damage induced by H₂O₂, and moreover, BK treatment significantly prevented reactive oxygen species (ROS) production in H9C2 cells treated with H₂O₂. Importantly, when co-incubated with bradykinin B2 receptor antagonist HOE-140 or eNOS inhibitor N-methyl-L-arginine acetate salt (L-NAME), the protective effects of bradykinin on H9C2 senescence were totally blocked. Furthermore, BK administration significantly prevented the increase in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity characterized by increased ROS generation and gp91 expression and increased translocation of p47 and p67 to the membrane and the decrease in superoxide dismutase (SOD) activity and expression induced by H₂O₂ in H9C2 cells, which was dependent on BK B2 receptor mediated nitric oxide (NO) release.</p><p>Conclusions</p><p>Bradykinin, acting through BK B2 receptor induced NO release, upregulated antioxidant Cu/Zn-SOD and Mn-SOD activity and expression while downregulating NADPH oxidase activity and subsequently inhibited ROS production, and finally protected against cardiomyocytes senescence induced by oxidative stress.</p></div

Effects of BK on DNA damage in H9C2 cells treated with H₂O₂.

<p>A, Left, control (without H₂O₂); right, 24 hours after stimulation with 30 µmol/L of H₂O₂ for 2 hours. Olive tail moment is calculated as a percentage of DNA in the tail distance to center of gravity of tail. Bars represent means ±SEM (*<i>P</i><0.05 vs control; ^#<i>P</i><0.05 vs H₂O₂; n = 3 experiments).</p

Effects of BK B2 receptor antagonist and eNOS inhibitor on the protective effect of BK against H9C2 cells senescence.

<p>Senescence was measured as the number of sa-β-gal–positive cells 3 days after treatment with H₂O₂. A, effect of BK B2 receptor antagonist HOE-140 on the protective effect of BK against H9C2 cells senescence. B, effect of L-NAME on the protective effect of BK against H9C2 cells senescence. Bars represent means ±SEM (*<i>P</i><0.05 vs control; ^#<i>P</i><0.05 vs H₂O₂; ^&<i>P</i><0.05 vs H₂O₂+BK; n = 6).</p