Endophilin B1 is a member of the Endophilin family and has been shown to be involved in apoptosis, mitochondrial morphological changes and autophagy. Although Endophilin B1 is highly expressed in the heart, its role in the maintenance of normal cardiac function and myocardial ischemia and reperfusion (I/R) injury remains unclear. Here, we found that Endophilin B1 deletion provoked spontaneous cardiac contractile dysfunction, cardiac hypertrophy and fibrosis at 16 weeks of age. Moreover, at 8 weeks of age, although spontaneous cardiac dysfunction in Endophilin B1 deletion mice had not developed, the deletion of Endophilin B1 exacerbated I/R-induced cardiac contractile dysfunction and cardiomyocyte death, whereas restoration of Endophilin B1 expression in the heart reduced I/R injury. Furthermore, we discovered that Endophilin B1 is indispensable for maintaining normal mitochondrial structure and function. In addition, we found that Endophilin B1 is localized in extracellular mitochondrion-containing vesicles and is required for mitocytosis, a process by which damaged mitochondria are disposed through extracellular vesicles. In conclusion, our study identified Endophilin B1 as an essential mitocytosis regulator for maintaining mitochondrial homeostasis and cardiac function. These findings suggest that Endophilin B1 is a novel therapeutic target for cardiac disorders such as I/R injury, myocardial infarction and heart failure.

AIMS:βII spectrin is a cytoskeletal protein known to be tightly linked to heart development and cardiovascular electrophysiology. However, the roles of βII spectrin in cardiac contractile function and pathological post-myocardial infarction remodelling remain unclear. Here, we investigated whether and how βII spectrin, the most common isoform of non-erythrocytic spectrin in cardiomyocytes, is involved in cardiac contractile function and ischaemia/reperfusion (I/R) injury. METHODS AND RESULTS:We observed that the levels of serum βII spectrin breakdown products (βII SBDPs) were significantly increased in patients with acute myocardial infarction (AMI). Concordantly, βII spectrin was degraded into βII SBDPs by calpain in mouse hearts after I/R injury. Using tamoxifen-inducible cardiac-specific βII spectrin knockout mice, we found that deletion of βII spectrin in the adult heart resulted in spontaneous development of cardiac contractile dysfunction, cardiac hypertrophy, and fibrosis at 5 weeks after tamoxifen treatment. Moreover, at 1 week after tamoxifen treatment, although spontaneous cardiac dysfunction in cardiac-specific βII spectrin knockout mice had not developed, deletion of βII spectrin in the heart exacerbated I/R-induced cardiomyocyte death and heart failure. Furthermore, restoration of βII spectrin expression via adenoviral small activating RNA (saRNA) delivery into the heart reduced I/R injury. Immunoprecipitation coupled with mass spectrometry (IP-LC-MS/MS) analyses and functional studies revealed that βII spectrin is indispensable for mitochondrial complex I activity and respiratory function. Mechanistically, βII spectrin promotes translocation of NADH:ubiquinone oxidoreductase 75-kDa Fe-S protein 1 (NDUFS1) from the cytosol to mitochondria by crosslinking with actin filaments (F-actin) to maintain F-actin stability. CONCLUSION:βII spectrin is an essential cytoskeletal element for preserving mitochondrial homeostasis and cardiac function. Defects in βII spectrin exacerbate cardiac I/R injury.

Mammalian mitochondrial DNA (mtDNA) encodes a total of 13 proteins, all of which are subunits of enzyme complexes of the oxidative phosphorylation. The mtDNA-encoded protein synthesis depends on the mitochondrial ribosomal proteins (MRPs), which assemble to form a specialized form of ribosome. Some mtDNA-encoded proteins have been reported to be reduced after myocardial ischemic injury. However, the molecular mechanisms responsible for this decrease and whether this decrease is involved in myocardial ischemia/reperfusion (I/R) injury remains unknown. Here, we found that the mtDNA-encoded protein levels were significantly decreased after I/R injury, while the mRNA levels of these genes were either increased or had no significant change. Subsequently, by querying and analyzing public database resources, we found that the expression of many mitochondrial translation-related proteins tended to decrease after myocardial infarction injury, and the reduction in the expression of these proteins was most obvious for Mrpl42. Furthermore, we found that cardiac Mrpl42 knockdown aggravated I/R-induced cardiac contractile dysfunction and cardiomyocyte death, while restoring Mrpl42 expression in the heart reduced I/R injury. Mrpl42 knockdown impaired the translation of mtDNA-encoded genes, ultimately led to aberrations in mitochondrial morphology and respiratory function. In addition, we found that the decrease in the expression of Mrpl42 after I/R injury was caused by the downregulation of Nrf2, which directly regulates Mrpl42 transcription. Our study revealed that ischemic downregulation of Mrpl42 expression and subsequent inhibition of mitochondrial translation contribute to cardiac I/R injury. Targeting Mrpl42 may be a novel therapeutic intervention for cardiac I/R injury and myocardial infarction.

The mitochondrial oxidative phosphorylation system is a major source of mitochondrial injury during myocardial ischemia and reperfusion. Mitochondrial ribosomal proteins (MRPs) assemble as specialized ribosomes to synthesize mtDNA-encoded proteins, which are subunits of enzyme complexes of the oxidative phosphorylation system. Some mtDNA-encoded proteins have been reported to be reduced after myocardial ischemic injury. However, the molecular mechanisms responsible for this decrease remain to be identified. Here, we found that many mitochondrial translation-related proteins showed a decreasing expression trend after MI injury, of which the reduction was most obvious in Mrpl42. Furthermore, we found that cardiac Mrpl42 knockdown aggravated I/R-induced cardiac contractile dysfunction, cardiomyocyte death and oxidative stress, while restoration of Mrpl42 expression in the heart reduced I/R injury. Mrpl42 knockdown impairs the translation of mtDNA-encoded genes, ultimately leading to aberrations in mitochondrial morphology and mitochondrial respiratory dysfunction. In addition, we found that the decreased expression of Mrpl42 after I/R injury was caused by the downregulation of NRF2 because NRF2 directly regulated Mrpl42 transcription. Our study identified that ischemic downregulation of Mrpl42 expression and subsequent inhibition of mitochondrial translation contribute to cardiac I/R injury via the suppression of mitochondrial function. Targeting Mrpl42 may be a novel therapeutic intervention against I/R injury and myocardial infarction.

Brain natriuretic peptide (BNP) belongs to the family of natriuretic peptides, which are responsible for a wide range of actions. Diabetic cardiomyopathy (DCM) is often associated with increased BNP levels. This present research intends to explore the role of BNP in the development of DCM and the underlying mechanisms. Diabetes was induced in mice using streptozotocin (STZ). Primary neonatal cardiomyocytes were treated with high glucose. It was found that the levels of plasma BNP started to increase at 8 weeks after diabetes, which preceded the development of DCM. Addition of exogenous BNP promoted Opa1-mediated mitochondrial fusion, inhibited mitochondrial oxidative stress, preserved mitochondrial respiratory capacity and prevented the development of DCM, while knockdown of endogenous BNP exacerbated mitochondrial dysfunction and accelerated DCM. Opa1 knockdown attenuated the aforementioned protective action of BNP both in vivo and in vitro. BNP-induced mitochondrial fusion requires the activation of STAT3, which facilitated Opa1 transcription by binding to its promoter regions. PKG, a crucial signaling biomolecule in the BNP signaling pathway, interacted with STAT3 and induced its activation. Knockdown of NPRA (the receptor of BNP) or PKG blunted the promoting effect of BNP on STAT3 phosphorylation and Opa1-mediated mitochondrial fusion. The results of this study demonstrate for the first time that there is a rise in BNP during the early stages of DCM as a compensatory protection mechanism. BNP is a novel mitochondrial fusion activator in protecting against hyperglycemia-induced mitochondrial oxidative injury and DCM through the activation of NPRA-PKG-STAT3-Opa1 signaling pathway.

Background Diabetic cardiomyopathy (DCM) has been considered as a major threat to health in individuals with diabetes. GrpE-like 2 (Grpel2), a nucleotide exchange factor, has been shown to regulate mitochondrial import process to maintain mitochondrial homeostasis. However, the effect and mechanism of Grpel2 in DCM remain unknown. Methods The streptozotocin (STZ)-induced DCM mice model and high glucose (HG)-treated cardiomyocytes were established. Overexpression of cardiac-specific Grpel2 was performed by intramyocardial injection of adeno-associated virus serotype 9 (AAV9). Bioinformatics analysis, co-immunoprecipitation (co-IP), transcriptomics profiling and functional experiments were used to explore molecular mechanism of Grpel2 in DCM. Results Here, we found that Grpel2 was decreased in DCM induced by STZ. Overexpression of cardiac-specific Grpel2 alleviated cardiac dysfunction and structural remodeling in DCM. In both diabetic hearts and HG-treated cardiomyocytes, Grpel2 overexpression attenuated apoptosis and mitochondrial dysfunction, including decreased mitochondrial ROS production, increased mitochondrial respiratory capacities and increased mitochondrial membrane potential. Mechanistically, Grpel2 interacted with dihydrolipoyl succinyltransferase (DLST), which positively mediated the import process of DLST into mitochondria under HG conditions. Furthermore, the protective effects of Grpel2 overexpression on mitochondrial function and cell survival were blocked by siRNA knockdown of DLST. Moreover, Nr2f6 bond to the Grpel2 promoter region and positively regulated its transcription. Conclusion Our study provides for the first time evidence that Grpel2 overexpression exerts a protective effect against mitochondrial dysfunction and apoptosis in DCM by maintaining the import of DLST into mitochondria. These findings suggest that targeting Grpel2 might be a promising therapeutic strategy for the treatment of patients with DCM.

The atrial natriuretic peptide (ANP) and the brain natriuretic peptide (BNP) are critical biological makers and regulators of cardiac functions. Our previous results show that NPRA (natriuretic peptide receptor A)-deficient mice have distinct metabolic patterns and expression profiles compared with the control. Still, the molecular mechanism that could account for this observation remains to be elucidated. Here, methylation alterations were detected by mazF-digestion, and differentially expressed genes of transcriptomes were detected by a Genome Oligo Microarray using the myocardium from NPRA-deficient (NPRA-/-) mice and wild-type (NPRA+/+) mice as the control. Comprehensive analysis of m6A methylation data gave an altered landscape of m6A modification patterns and altered transcript profiles in cardiac-specific NPRA-deficient mice. The m6A "reader" igf2bp3 showed a clear trend of increase, suggesting a function in altered methylation and expression in cardiac-specific NPRA-deficient mice. Intriguingly, differentially m6A-methylated genes were enriched in the metabolic process and insulin resistance pathway, suggesting a regulatory role in cardiac metabolism of m6A modification regulated by NPRA. Notably, it was confirmed that the pyruvate dehydrogenase kinase 4 (Pdk4) gene upregulated the gene expression and the hypermethylation level simultaneously, which may be the key factor for the cardiac metabolic imbalance and insulin resistance caused by natriuretic peptide signal resistance. Taken together, cardiac metabolism might be regulated by natriuretic peptide signaling, with decreased m6A methylation and a decrease of Pdk4.

目的 研究糖蛋白M6B（glycoprotein M6B,GPM6B）对巨噬细胞炎症因子IL-1β、TNF-α、IFN-γ和IL-6的影响。方法 （1）Western blot和qPCR检测RAW264.7经典激活的巨噬细胞（classically activated macrophage,M1）和替代激活的巨噬细胞（alternatively activated macrophage, M2）中GPM6B表达量变化。（2）分别用对照组（shScramble）和GPM6B干涉组（sh-GPM6B1和sh-GPM6B2）的慢病毒感染RAW264.7巨噬细胞系，荧光显微镜下观察病毒的感染效率。Western blot和qPCR检测GPM6B的干涉效率。（3）qPCR检测对照组和GPM6B干涉组促炎因子IL-1β、TNF-α和IFN-γ的mRNA表达水平，ELISA法检测上清中IL-1β和IL-6的含量。（4）Western blot检测干涉GPM6B后炎症相关分子p65和Iκα的磷酸化水平变化。结果 （1）相比于对照组，RAW264.7巨噬细胞M1型中GPM6B蛋白和mRNA水平均显著升高（P＜0.05），而M2型中GPM6B蛋白和mRNA水平均显著降低（P＜0.05）。（2）与sh-Scramble组相比，sh-GPM6B1组和sh-GPM6B2组GPM6B蛋白和m RNA水平均显著降低（P＜0.05）。（3）干涉GPM6B后促炎因子IL-1β、TNF-α和IFN-γ的m RNA表达水平和上清中IL-1β和IL-6均显著降低（P＜0.05）。（4）干涉GPM6B后炎症相关分子p65和Iκα的磷酸化水平降低。结论 干涉GPM6B可抑制RAW264.7巨噬细胞促炎因子的表达。

Mitochondrial calcium ([Ca2+]m) overload is considered a major trigger of cardiomyocyte death during myocardial ischemia/reperfusion (I/R) injury. Grpel2 is located in mitochondria and facilitates the mtHSP70 protein folding cycle in oxidative stress. However, Grpel2 expression during I/R injury and its impact on I/R injury remain poorly understood. This study explored the role of Grpel2 in I/R injury and its underlying mechanism. Mice were intramyocardially injected with recombinant adenovirus vectors to knockdown cardiac Grpel2 expression, and a myocardial I/R model was established. We confirmed that cardiac Grpel2 is upregulated during I/R injury. Cardiac-specific Grpel2 knockdown exacerbates mitochondrial fission, cardiomyocyte death and cardiac contractile dysfunction induced by I/R injury. Moreover, our study revealed that Grpel2 knockdown increased both MCU expression and [Ca2+]m content. Excessive mitochondrial fission and apoptosis were rescued by Ru360, an inhibitor of MCU opening. In summary, our findings suggest that Grpel2 alleviates myocardial ischemia/reperfusion injury by inhibiting MCU-mediated mitochondrial calcium overload and provide new insights into the mechanism of MCU-mediated [Ca2+]m homeostasis during I/R injury.

目的 研究血影蛋白βⅡ（Spectrin βⅡ）在棕榈酸诱导的小鼠原代心肌细胞DNA损伤和细胞凋亡中的作用。方法 （1）Western blot检测棕榈酸处理后小鼠原代心肌细胞Spectrin βⅡ表达量变化。（2）分别用Ad-shscramble（对照组）和Ad-sh-Spectrin βⅡ（Spectrin βⅡ干涉组）的腺病毒感染小鼠原代心肌细胞，荧光显微镜下观察病毒的感染效率。利用Western blot和qPCR检测Spectrin βⅡ的干涉效率。（3）Western blot检测棕榈酸处理后Ad-sh-scramble组和Spectrin βⅡ干涉组小鼠原代心肌细胞DNA损伤指标γ-H2AX及凋亡蛋白剪切型半胱天冬酶3（cleaved-caspase 3）的表达，采用流式细胞术检测各组细胞凋亡水平。结果 （1）给予棕榈酸处理的小鼠原代心肌细胞Spectrin βⅡ蛋白水平显著降低（P＜0.05）。（2）与Ad-sh-scramble组相比，Ad-sh-Spectrin βⅡ组Spectrin βⅡ的蛋白和mRNA水平均显著降低（P＜0.05）（3）给予棕榈酸处理后，与Ad-sh-scramble组相比，Ad-sh-Spectrin βⅡ组的γ-H2AX2和cleaved-caspase 3蛋白表达显著升高（P＜0.05），并且细胞凋亡率显著升高（P＜0.05）。结论 敲低Spectrin βⅡ加重棕榈酸诱导的小鼠原代心肌细胞DNA损伤和细胞凋亡。

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are important biological markers and cardiac function regulators. Natriuretic peptide receptor A (NPRA) binds to an ANP or BNP ligand and induces transmembrane signal transduction by elevating the intracellular cyclic guanosine monophosphate (cGMP) levels. However, the metabolic phenotype and related mechanisms induced by NPRA deletion remain ambiguous. Here, we constructed myocardial-specific NPRA deletion mice and detected the heart functional and morphological characteristics by histological analysis and explored the altered metabolic pattern and the expression patterns of proteins by liquid chromatography-mass spectrometry (LC-MS)-based omics technology. NPRA deficiency unexpectedly did not result in significant cardiac remodeling or dysfunction. However, compared with the matched littermates, NPRA-deficient mice had significant metabolic differences. Metabolomic analysis showed that the metabolite levels varied in cardiac tissues and plasma. In total, 33 metabolites were identified in cardiac tissues and 54 were identified in plasma. Compared with control mice, NPRA-deficient mice had 20 upregulated and six downregulated metabolites in cardiac tissues and 25 upregulated and 23 downregulated metabolites in plasma. Together, NPRA deficiency resulted in increased nucleotide biosynthesis and histidine metabolism only in heart tissues and decreased creatine metabolism only in plasma. Further proteomic analysis identified 136 differentially abundant proteins in cardiac tissues, including 54 proteins with higher abundance and 82 proteins with lower abundance. Among them, cytochrome c oxidase subunit 7c and 7b (Cox7c, Cox7b), ATP synthase, H+ transporting, mitochondrial Fo complex subunit F2 (ATP5J2), ubiquinol-cytochrome c reductase, complex III subunit X (Uqcr10), and myosin heavy chain 7 (Myh7) were mainly involved in related metabolic pathways. These results revealed the essential role of NPRA in metabolic profiles and may elucidate new underlying pathophysiological mechanisms of NPRA in cardiovascular diseases.

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are important biological markers and regulators of cardiac function. The natriuretic peptide receptor A (NPRA), also known as NPR1 or guanylyl cyclase A, binds ANP and BNP to initiate transmembrane signal transduction by elevating the intracellular levels of cyclic guanosine monophosphate. However, the effects and mechanisms downstream of NPRA are largely unknown. The aim of the present study was to evaluate the changes in the global pattern of mRNA and circular RNA (circRNA) expression in NPRA‑/‑ and NPRA+/+ myocardium. Differentially expressed mRNA molecules were characterised using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis and were found to be primarily related to metabolic processes. Moreover, circRNA expression was also examined, and a possible competing endogenous RNA network consisting of circRNA, microRNA (miRNA), and mRNA molecules was constructed. The results of this study indicated that NPRA may play a role in cardiac metabolism, which could be mediated by circRNA through endogenous competition mechanisms. These findings may provide insight into future characterisation of various ceRNA network pathways.

Isoprenaline-induced cardiac hypertrophy can deteriorate to heart failure, which is a leading cause of mortality. Endogenous vasonatrin peptide (VNP) has been reported to be cardioprotective against myocardial ischemia/reperfusion injury in diabetic rats. However, little is known about the effect of exogenous VNP on cardiac hypertrophy. We further explored whether VNP attenuated isoprenaline-induced cardiomyocyte hypertrophy by examining the levels and activities of cGMP and PKG. In this study, we found that VNP significantly attenuated isoprenaline-induced myocardial hypertrophy and cardiac fibroblast activation in vivo. Moreover, VNP effectively halted the activation of apoptosis and oxidative stress in the isoprenaline-treated myocardium. VNP promoted superoxide dismutase (SOD) activity. Further study revealed that the protective effects of VNP might be mediated by the activity of the cGMP-PKG signaling pathway in vivo or in vitro, while the use of agonists and antagonists confirmed these results. Therefore, we demonstrated that the antiapoptosis and antioxidative stress effects of VNP depends on elevated cGMP-PKG signaling activity both in vivo and in vitro. These results suggest that VNP may be used in the treatment of myocardial hypertrophy.

目的:探讨利拉鲁肽对老年2型糖尿病合并高脂血症患者的内皮功能和免疫功能的影响.方法:选取我院2018年1月至2019年2月全科医学科门诊和住院收治的86例老年糖尿病合并高脂血症患者,随机分为对照组和利拉鲁肽组,各组43例,对照组采用二甲双胍治疗方法,利拉鲁肽组在此基础上进行皮下注射利拉鲁肽,两组患者连续观察2个月.分别在研究前后进行血糖和血脂的检测[血糖(FBG)、餐后2h血糖(2h PG)、糖化血红蛋白(HbA1c)、血脂总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白(LDL-C)、高密度脂蛋白(HDL-C)及体重指数(BMI)],比较内皮功能的指标(ET-1和NO)以及免疫功能[超敏C反应蛋白(hs-CRP),IgM和IgG].结果:利拉鲁肽组治疗后较对照组治疗后FBG、2h PG、TC和TG降低(P<0.05);利拉鲁肽组治疗后与对照组治疗后HbA1c、LDL-C、HDL-C和BMI相比无统计学意义(P>0.05).利拉鲁肽组治疗后ET-1较治疗前显著降低(P<0.01);利拉鲁肽组治疗后NO较治疗前无统计学意义(P>0.05);利拉鲁肽组治疗后ET-1水平较对照组治疗后降低(P<0.05),利拉鲁肽组治疗后NO水平较对照组升高(P<0.05).利拉鲁肽组治疗后较对照组治疗后hs-CRP降低,而IgG较对照组升高(P<0.05).结论:利拉鲁肽对老年2型糖尿病合并高脂血症降脂效果更明显,可以缓解内皮功能的损伤,增加免疫功能,降低炎症反应.

Brain natriuretic peptide (BNP) is an important biological marker and regulator of cardiac function. BNP resistance is characterized by high concentrations of less functionally effective BNP and common in heart failure (HF) patients. However, the roles and consequences of BNP resistance remain poorly understood. Investigate the effects of cardiac BNP resistance and identify potential metabolic biomarkers for screening and diagnosis. Thirty patients and thirty healthy subjects were enrolled in this study. Cardiac functions were evaluated by echocardiography. The plasma levels of cyclic guanosine monophosphate (cGMP) and BNP were measured by enzyme-linked immunosorbent assay (ELISA) and the cGMP/BNP ratio is calculated to determine cardiac natriuretic peptide resistance. Liquid chromatograph tandem mass spectrometry (LC-MS) based untargeted metabolomics analysis was applied to screen metabolic changes. The cGMP/BNP ratio was markedly lower in HF patients than controls. The cGMP/BNP ratio and ejection fraction (EF) were strongly correlated (R2 = 0.676, P < 0.05 ). Importantly, metabolic profiles were substantially different between HF patients and healthy controls. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis demonstrated that the differentially expressed metabolites are involved in signaling pathways that regulate cardiac functions. In HF patients, BNP resistance develops in association with a reduction in heart function and metabolic remodeling. It suggests possible functional roles of BNP resistance in the regulation of cardiac metabolism.

Branched chain aminoacids (BCAAs) are associated with the progression of obesity-related metabolicdisorders, including T2DM and non-alcoholic fatty liver disease. However, whetherBCAAs disrupt the homeostasis of hepatic glucose and lipid metabolism remainsunknown. In this study, we observed that BCAAs supplementation significantlyreduced high-fat (HF) diet-induced hepatic lipid accumulation while increasing the plasmalipid levels and promoting muscular and renal lipid accumulation. Furtherstudies demonstrated that BCAAs supplementation significantly increased hepaticgluconeogenesis and suppressed hepatic lipogenesis in HF diet-induced obese(DIO) mice. These phenotypes resulted from severe attenuation of Akt2 signalingvia mTORC1- and mTORC2-dependent pathways. BCAAs/branched-chain α-keto acids(BCKAs) chronically suppressed Akt2 activation through mTORC1 and mTORC2signaling and promoted Akt2 ubiquitin-proteasome-dependent degradation through the mTORC2 pathway.Moreover, the E3 ligase Mul1 played an essential role in BCAAs/BCKAs-mTORC2-inducedAkt2 ubiquitin-dependent degradation. We also demonstrated that BCAAs inhibited hepaticlipogenesis by blocking Akt2/SREBP1/INSIG2a signaling and increased hepaticglycogenesis by regulating Akt2/Foxo1 signaling. Collectively, these datademonstrate that in DIO mice, BCAAs supplementation resulted in serious hepaticmetabolic disorder and severe liver insulin resistance: insulin failed to notonly suppress gluconeogenesis but also activate lipogenesis. Intervening BCAAmetabolism is a potential therapeutic target for severe insulin-resistant disease.

The purpose of the present study was to explore aging-associated cardiac dysfunction and the possible mechanism by which swimming exercise modulates cardiac dysfunction in aged mice. Aged mice were divided into two groups: i) Aged mice; and ii) aged mice subjected to swimming exercises. Another cohort of 4-month-old male mice served as the control group. Cardiac structure and function in mice were analyzed using hematoxylin and eosin staining, and echocardiography. The levels of oxidative stress were determined by measuring the levels of superoxide dismutase, malondialdehyde and reactive oxygen species (ROS). Levels of the endoplasmic reticulum (ER) stress-related protein PKR-like ER kinase, glucose-regulated protein 78 and C/EBP homologous protein were determined to evaluate the level of ER stress. The aged group exhibited an abnormal cardiac structure and decreased cardiac function, both of which were ameliorated by swimming exercise. The hearts of the aged mice exhibited pronounced oxidative and ER stress, which were ameliorated by exercise, and was accompanied by the reactivation of myocardial cGMP and suppression of cGMP-specific phosphodiesterase type 5 (PDE5). The inhibition of PDE5 attenuated age-induced cardiac dysfunction, blocked ROS production and suppressed ER stress. An ER stress inducer abolished the beneficial effects of the swimming exercise on cardiac function and increased ROS production. The present study suggested that exercise restored cardiac function in mice with age-induced cardiac dysfunction by inhibiting oxidative stress and ER stress, and increasing cGMP-protein kinase G signaling.

Objective To investigate the regulatory effect of branched chain amino acids (BCAA) on the expression of apoptosis related proteins after cerebral ischemia reperfusion injury and the protective effects of BCAA on ischemic brain injury in rats.Methods 40 male SD rats were randomly divided into normal diet group (n =20) and branched chain amino acid (BCAA) group (n=20) according to the random number table,and each group was randomly divided into control group (n=6),sham operation group (n=6) and model group (n =8) which used suture method to make ischemia reperfusion model.After modeling,modified Neurological Severity Scores (mNSS) was used to access the neurological impairment degree of 2,6,24,48 and 72 h in each group.The expression of apoptosis related proteins (Cleaved,Bax/Bcl-2) after 72 h was detected by the method of immune protein imprinting (Caspase3) and compared between normal diet group and BCAA group.Results Compared with the normal diet rats,the mNSS of BCAA diet rats after modeling at 2,6,24,48,72 h decreased (11.35±2.78 vs.7.15±2.41,P=0.019;9.35±1.75 vs.5.82±1.17,P=0.002;6.11±1.16vs.4.39±1.46,P=0.048;5.87±1.32vs.3.55±1.94,P=0.036;4.98±2.24vs.2.09±1.33,P=0.022).The expression of cleaved caspase3 protein and the ratio of Bax/Bcl-2 decreased in BCAA group.Conclusion BCAA can alleviate the apoptosis of rats after ischemia and reperfusion,reduce the damage of nerve function,and has a positive protective effect on ischemic brain injury.

目的 观察鸢尾素(Irisin)对缺氧复氧处理后H9C2心肌细胞的保护作用.方法 将大鼠H9C2心肌细胞分为对照组、对照+Irisin组、缺氧复氧组、缺氧复氧+Irisin组.对照组正常培养,对照+Irisin组正常培养并给予10 ng/mL的Irisin,缺氧复氧组细胞行缺氧复氧处理,缺氧复氧+Irisin组细胞进行缺氧复氧处理后再加入10 ng/mL的Irisin.通过CCK-8检测心肌细胞活力,活性氧(ROS)荧光探针检测细胞内ROS含量,流式细胞术检测线粒体膜电位JC-1.利用RT-PCR检测心肌细胞caspase-3和caspase-9的mRNA含量.结果 缺氧复氧组细胞活力显著低于对照组(P＜0.01);缺氧复氧+Irisin组细胞活力高于缺氧复氧组(P＜0.05).缺氧复氧组细胞内ROS水平高于对照组(P＜0.01);缺氧复氧+Irisin组ROS水平低于缺氧复氧组(P＜ 0.05).缺氧复氧组线粒体膜电位JC-1水平低于对照组(P＜0.05);缺氧复氧+Irisin组线粒体膜电位JC-1水平高于缺氧复氧组(P＜0.05).缺氧复氧组caspase-3及caspase-9的mRNA水平高于对照组(P＜0.05);缺氧复氧+Irisin组caspase-3及caspase-9的mRNA水平低于缺氧复氧组(P＜0.05).结论 Irisin可提高心肌细胞缺氧复氧处理后的细胞活力,减少ROS生成,恢复线粒体膜电位,抑制凋亡通路,可作为改善心肌缺血再灌注损伤的潜在治疗药物.

目的:探讨阿托伐他汀对2型糖尿病心肌病心功能、脑钠肽(BNP)及超敏C反应蛋白(hs-CRP)的影响.方法:将59例2型糖尿病心肌病患者随机分为一般治疗组(n=29例)和阿伐他汀治疗组(n=30例),一般治疗组和阿伐他汀治疗组在治疗中严格控制血糖及给予抗心衰规范化治疗,阿伐他汀治疗组在此治疗基础上,加用阿伐他汀(20 mg/d)治疗.所有患者在治疗前和治疗8周后,左室射血分数(LVEF)、检测左室舒张末期内径(LVDd)、血浆脑钠肽前体检氨基端片段(BNP)和血清超敏C反应蛋白(hs-CRP).结果:两组患者在治疗前LVEF、LVDd、BNP及hs-CRP差异均无统计学意义(P>0.05),经8周治疗后,一般治疗组和阿托伐他汀治疗组,LVEF较治疗前明显改善(P<0.05),BNP及HS-CRP水平较治疗前明显降低(P<0.05),但LVDd未见明显改善(P>0.05),两组患者在治疗后,阿托伐他汀治疗组较一般治疗组BNP及hs-CRP明显降低(P<0.05),但LVEF和LVDd没有显著变化(P>0.05).结论:阿托伐他汀改善糖尿病心肌病心功能,可能与降低血浆中脑钠肽水平及炎症因子相关.