Cardiac inotropy, lusitropy, and Ca ²⁺ handling with major metabolic substrates in rat heart

Zhao, Zai Hao,Youm, Jae Boum,Wang, Yue,Lee, Jeong Hoon,Sung, Jae Hwi,Kim, Joon-Chul,Woo, Sun Hee,Leem, Chae Hun,Kim, Sung Joon,Cui, Lan,Zhang, Yin Hua Springer Berlin Heidelberg 2016 Pfl ugers Arch Vol.468 No.11

<P>Fatty acid (FA)-dependent oxidation is the predominant process for energy supply in normal heart. Impaired FA metabolism and metabolic insufficiency underlie the failing of the myocardium. So far, FA metabolism in normal cardiac physiology and heart failure remains undetermined. Here, we evaluate the mechanisms of FA and major metabolic substrates (termed NF) on the contraction, relaxation, and Ca<SUP>2+</SUP> handling in rat left ventricular (LV) myocytes. Our results showed that NF significantly increased myocyte contraction and facilitated relaxation. Moreover, NF increased the amplitudes of diastolic and systolic Ca<SUP>2+</SUP> transients ([Ca<SUP>2+</SUP>]<SUB>i</SUB>), abbreviated time constant of [Ca<SUP>2+</SUP>]<SUB>i</SUB> decay (tau), and prolonged the peak duration of [Ca<SUP>2+</SUP>]<SUB>i</SUB>. Whole-cell patch-clamp experiments revealed that NF increased Ca<SUP>2+</SUP> influx via L-type Ca<SUP>2+</SUP> channels (LTCC, I<SUB>Ca-integral</SUB>) and prolonged the action potential duration (APD). Further analysis revealed that NF shifted the relaxation phase of sarcomere lengthening vs. [Ca<SUP>2+</SUP>]<SUB>i</SUB> trajectory to the right and increased [Ca<SUP>2+</SUP>]<SUB>i</SUB> for 50 % of sarcomere relengthening (EC<SUB>50</SUB>), suggesting myofilament Ca<SUP>2+</SUP> desensitization. Butanedione monoxime (BDM), a myosin ATPase inhibitor that reduces myofilament Ca<SUP>2+</SUP> sensitivity, abolished the NF-induced enhancement of [Ca<SUP>2+</SUP>]<SUB>i</SUB> amplitude and the tau of [Ca<SUP>2+</SUP>]<SUB>i</SUB> decay, indicating the association of myofilament Ca<SUP>2+</SUP> desensitization with the changes in [Ca<SUP>2+</SUP>]<SUB>i</SUB> profile in NF. NF reduced intracellular pH ([pH<SUB>i</SUB>]). Increasing [pH]<SUB>i</SUB> buffer capacity with HCO<SUB>3</SUB>/CO<SUB>2</SUB> attenuated Δ [pH]<SUB>i</SUB> and reversed myofilament Ca<SUP>2+</SUP> desensitization and Ca<SUP>2+</SUP> handling in NF. Collectively, greater Ca<SUP>2+</SUP> influx through LTCCs and myofilament Ca<SUP>2+</SUP> desensitization, via reducing [pH]<SUB>i</SUB>, are likely responsible for the positive inotropic and lusitropic effects of NF. Computer simulation recapitulated the effects of NF.</P><P><B>Electronic supplementary material</B></P><P>The online version of this article (doi:10.1007/s00424-016-1892-8) contains supplementary material, which is available to authorized users.</P>

Microscopic Study on the Mechanism of Tool Bond Wear in Cutting Ni–Fe-Cr-Co–Cu Series Nickel-Base Superalloy

Zhao Peng Hao,Xue Han,Yi Hang Fan,Zai Zhen Lou 한국정밀공학회 2021 International Journal of Precision Engineering and Vol.22 No.4

In the process of nickel-based alloy machining, chips are easy to bond on the tool surface, which weaken the tool performance and make the tool wear. Therefore, it is very important to study the mechanism of tool bond wear in the process of nickel-based superalloy machining. In order to reflect the wear process of the tool from the perspective of micro cutting, the molecular dynamics simulation model for cutting Ni–Fe-Cr-Co–Cu nickel-based alloy with SiC tool was established. The Morse potential functions between the tool and workpiece are calculated, and the simulation results are analyzed visually. It is found that the bond wear is the main wear form of tool in the process of cutting nickel-based alloy, and the wear processes are divided into three stages: contact, adhesion and shedding. The stress and strain in the cutting area are calculated and it is found that the bond occurs when the tool-workpiece extrusion is strong. Through the calculation of radial distribution function and formation energy, it is found that Ni-Si compound is formed on the tool surface, and the newly generated Ni-Si compound reduces the tool performance compared with the silicon carbide structure. This study provides a more complete microscopic explanation of the tool wear mechanism, which is helpful to find a method to prolong tool life.

S-nitrosylation of transglutaminase 2 impairs fatty acid-stimulated contraction in hypertensive cardiomyocytes

정의만,Chun Zi Jin,장지현,Zai Hao Zhao,Chun Li Jin,이진항,이기백,김성준,김인규,Yin Hua Zhang 생화학분자생물학회 2018 Experimental and molecular medicine Vol.50 No.-

The myocardium in hypertensive heart exhibits decreased fatty acid utilization and contractile dysfunction, leading to cardiac failure. However, the causal relationship between metabolic remodeling and cardiomyocyte contractility remains unestablished. Transglutaminase 2 (TG2) has been known to promote ATP production through the regulation of mitochondrial function. In this study, we investigated the involvement of TG2 in cardiomyocyte contraction under fatty acid supplementation. Using TG2 inhibitor and TG2-deficient mice, we demonstrated that fatty acid supplementation activated TG2 and increased ATP level and contractility of cardiac myocyte from the normal heart. By contrast, in cardiac myocytes from angiotensin-II-treated rats and mice, the effects of fatty acid supplementation on TG2 activity, ATP level, and myocyte contraction were abolished. We found that TG2 was inhibited by S-nitrosylation and its level increased in hypertensive myocytes. Treatment with inhibitor for neuronal NOS restored fatty acidinduced increase of TG2 activity and myocyte contraction. Moreover, intracellular Ca2+ levels were increased by fatty acid supplementation in both normal and hypertensive myocytes, showing that S-nitrosylation of TG2 but not alteration of intracellular Ca2+ levels is responsible for contractile dysfunction. These results indicate that TG2 plays a critical role in the regulation of myocyte contractility by promoting fatty acid metabolism and provide a novel target for preventing contractile dysfunction in heart with high workload.

Intravenous Tenecteplase for Acute Ischemic Stroke Within 4.5–24 Hours of Onset (ROSE-TNK): A Phase 2, Randomized, Multicenter Study

Wang Lu,Dai Ying-Jie,Cui Yu,Zhang Hong,Jiang Chang-Hao,Duan Ying-Jie,Zhao Yong,Feng Ye-Fang,Geng Shi-Mei,Zhang Zai-Hui,Lu Jiang,Zhang Ping,Zhao Li-Wei,Zhao Hang,Ma Yu-Tong,Song Cheng-Guang,Zhang Yi,Ch 대한뇌졸중학회 2023 Journal of stroke Vol.25 No.3

Background and Purpose Intravenous tenecteplase (TNK) efficacy has not been well demonstrated in acute ischemic stroke (AIS) beyond 4.5 hours after onset. This study aimed to determine the effect of intravenous TNK for AIS within 4.5 to 24 hours of onset. Methods In this pilot trial, eligible AIS patients with diffusion-weighted imaging (DWI)-fluid attenuated inversion recovery (FLAIR) mismatch were randomly allocated to intravenous TNK (0.25 mg/kg) or standard care within 4.5–24 hours of onset. The primary endpoint was excellent functional outcome at 90 days (modified Rankin Scale [mRS] score of 0–1). The primary safety endpoint was symptomatic intracranial hemorrhage (sICH). Results Of the randomly assigned 80 patients, the primary endpoint occurred in 52.5% (21/40) of TNK group and 50.0% (20/40) of control group, with no significant difference (unadjusted odds ratio, 1.11; 95% confidence interval 0.46–2.66; <i>P</i>=0.82). More early neurological improvement occurred in TNK group than in control group (11 vs. 3, <i>P</i>=0.03), but no significant differences were found in other secondary endpoints, such as mRS 0–2 at 90 days, shift analysis of mRS at 90 days, and change in National Institutes of Health Stroke Scale score at 24 hours and 7 days. There were no cases of sICH in this trial; however, asymptomatic intracranial hemorrhage occurred in 3 of the 40 patients (7.5%) in the TNK group. Conclusion This phase 2, randomized, multicenter study suggests that intravenous TNK within 4.5–24 hours of onset may be safe and feasible in AIS patients with a DWI-FLAIR mismatch.