小檗碱对实验性2型糖尿病心肌病大鼠模型心脏保护作用研究

目的 研究小檗碱(berberine)对实验性2型糖尿病心肌病(diabetic cardiomyopathy,DC)大鼠模型心脏的保护作用,并探讨作用机制.方法 高糖高脂膳食负荷小剂量链脲佐菌素(streptozotocin,STZ)诱导实验性2型DC大鼠模型,观察小檗碱对模型动物心脏功能、结构变化以及血浆、心肌组织糖脂代谢相关指标的作用.结果 小檗碱治疗6周后,可明显改善DC大鼠模型心脏收缩和舒张功能,降低左心室前壁厚度、室间隔厚度以及心肌组织胶原含量;另外,小檗碱可减少模型动物血糖、血脂以及心脏游离脂肪酸(nonesterified fatty acids,NEFA)含量,增加心肌组织脂肪酸跨膜转运载体蛋白(fatty acid transporters,FATPs)和脂肪酸β氧化酶(fatty acid β oxidase,FA-β-oxidase)含量.结论 小檗碱可改善糖尿病心肌病心脏舒张和收缩功能,抑制心肌肥厚和心室重构,作用机制可能与降低高血糖和高血脂状态、以及增加FATPs和FA-β-oxidase改善心肌内脂肪酸代谢紊乱有关.     

糖尿病心肌病的发病机制研究

糖尿病心肌病(DC)是排除了高血压性心脏病、冠状动脉粥样硬化心脏病、心脏瓣膜病及其他心脏病变所致的心肌损伤后诊断的一种特异性心肌病,是糖尿病的主要并发症之一。临床表现为心脏收缩和舒张功能障碍,最终导致心力衰竭、心律失常和猝死。目前的研究认为,心肌细胞的代谢紊乱、心脏微血管和自主神经病变及其他神经内分泌因素在DC的发生发展中均起了重要的作用,该文就DC的发病机制予以综述。     

糖代谢异常与心脏结构和功能改变的关系

糖代谢异常包括糖调节受损和糖尿病两大类型.糖调节受损是介于正常糖耐量和糖尿病之间的一组糖代谢异常状态,是糖尿病的前期阶段.目前大量研究表明,在发生糖尿病前有可能已存在程度不同的、与糖代谢异常相关的心脏病变的早期表现.本文综述不同糖代谢状态人群的心脏结构和功能的状况及其机制.     

心脏脂肪酸代谢抑制在孕期炎症刺激致子代小鼠心脏损伤中的作用及机制

目的研究孕期炎症刺激对子代心脏功能的影响及其疾病发生的具体机制。方法在C57小鼠孕期10.5 d时ip给予LPS和poly(I∶C)构建孕期炎症模型,用小动物超声仪对其子代不同时期(8,16和32周)的心功能进行检测,采用定量代谢组学和定量PCR对子代不同时期心脏代谢产物和相关基因进行分析。对筛选的靶基因进行敲除进一步验证其在子代心脏发病机制中的关键作用。结果实验结果,发现孕期炎症刺激导致子代心功能明显下降和心肌肥厚。进一步研究发现,子代心脏组织中脂肪酸氧化代谢酶(ACSL1)和上游关键转录调控因子(PPARγ)等基因表达下调,这将导致子代心脏脂肪酸氧化代谢抑制和脂肪酸积累,心脏组织能量供给不足引起糖脂代谢失衡及mTORC1信号通路持续活化,与子代后期心功能降低呈一致性。采用基因敲除技术抑制子代心脏mTORC1信号通路的持续活性,降低了子代心脏损伤。结论孕期炎症刺激子代心脏脂肪酸代谢抑制和mTORC1信号通路活性持续活化在孕期炎症刺激子代心脏损伤中具有关键作用。明确脂肪酸代谢抑制和mTORC1信号通路活性持续活化在其疾病模型中的作用及机制,将为阐明孕期炎症刺激致子代易患心血管疾病的分子机制提供新思路,并为寻找预防策略提供理论基础。     

AMPK信号通路在糖尿病心肌病中的研究进展

AMP依赖的蛋白激酶(AMPK)是调节生物能量恒定性的重要传感分子,能激活上游激酶LKB1、Ca MKKβ和Tak1等。AMP/ATP比值可调节AMPK的活性,从而控制能量代谢的分解与合成通路,骨骼肌收缩与心肌缺血时能够激活AMPK,调节脂肪细胞的代谢和血管功能,促进葡萄糖转运和脂肪酸氧化。排除动脉粥样硬化、高血压及其他潜在病因,由糖尿病引发的心肌结构与功能异常的一种独立的原发病,称之为糖尿病心肌病,可引起患者死亡。由于血糖水平、脂肪酸氧化和糖原代谢受AMPK的调节,因此,在DCM形成过程中AMPK起着至关重要的作用。该文综述了AMPK信号通路在糖尿病心肌病发生、发展过程中的作用。     

中医治未病理论与糖尿病性心脏病防治探讨

<正>糖尿病心脏病(Diabetic Cardiopathy,DC)病名由Ledet于1979年首先提出,目前在内分泌界得到普遍公认。糖尿病心脏病是糖尿病最重要的远期并发症之一,主要包括糖尿病心脏微血管病变、大血管病变、心肌病变、心脏植物神经功能紊乱所致的心     

肌钙蛋白Ⅰ、心脏型脂肪酸结合蛋白、NT-proBNP联合检测在急性冠状动脉综合征诊断中的应用价值

目的:探讨肌钙蛋白Ⅰ、心脏型脂肪酸结合蛋白、NT-proBNP联合检测在急性冠状动脉综合征诊断中的应用价值。方法:选取某院2013年6月~2016年6月收治的100例急性冠状动脉综合征患者作为观察组,选择同期我院体检中心体检的健康体检者100例作为对照组,对两组肌钙蛋白Ⅰ、心脏型脂肪酸结合蛋白和NT-proBNP进行检测及对比分析。结果:观察组肌钙蛋白Ⅰ、心脏型脂肪酸结合蛋白和NT-proBNP分别为(8.8±6.4)μg/L、(12.63±3.16)ng/L和(1385±251)ng/L,对照组肌钙蛋白Ⅰ、心脏型脂肪酸结合蛋白和NT-proBNP分别为(0.3±0.5)μg/L、(2.69±0.91)ng/L和(329±124)ng/L,观察组显著高于对照组(P均0.001)。结论:肌钙蛋白Ⅰ、心脏型脂肪酸结合蛋白和NT-proBNP在急性冠状动脉综合征患者中均表达上调,可作为急性冠状动脉综合征诊断和鉴别的指标。     

转录辅抑制因子RIP140在代谢组织中的作用及机制

核受体超家族在调节能量平衡过程中扮演重要角色。转录辅助调节因子通过募集一系列DNA或组蛋白结构修饰酶,调节核受体介导的靶基因转录。受体相互作用蛋白140(receptor-interacting protein140,RIP140)是一种转录辅抑制因子,其与核受体结合后能够负向调节多种代谢组织中靶基因的转录,包括脂肪组织、肌肉组织以及肝脏等。基因沉默RIP140后,多种代谢途径相关基因表达上调,主要涉及糖酵解、甘油三酯合成、三羧酸循环、脂肪酸β氧化、线粒体电子传递以及氧化磷酸化等能量代谢过程。RIP140有望成为治疗代谢综合征的候选靶点。     

氯沙坦对主动脉狭窄大鼠血清β_1肾上腺素受体与M_2毒蕈碱受体自身抗体产生的影响

采用缩窄主动脉复制心功能不全大鼠模型 ,动态观察 (10周 )氯沙坦 (术后第 2周开始 ,5mg·kg- 1·d- 1,ig ,连续 8周 )治疗对模型大鼠血清 β1肾上腺素受体 (β1受体 )与M2 毒蕈碱受体 (M2 受体 )自身抗体产生的影响 .结果表明 ,缩窄主动脉组血清中两种受体自身抗体从术后 1周起阳性率 ,滴度逐渐升高 ;给予氯沙坦治疗不仅可抑制模型大鼠心脏功能和结构的改变 ,而且使两种血清受体自身抗体的阳性率和滴度明显降低。结果提示氯沙坦有抑制心脏 β1与M2 受体自身抗体产生作用 .     

门冬胰岛素对妊娠期糖尿病的作用及对子代心脏结构和功能的影响

目的探究门冬胰岛素对妊娠期糖尿病(GDM)的治疗效果及对子代心脏结构和功能的影响。方法选择2016年1月至2017年1月我院收治的GDM患者50例为研究组,另选取同期行产检的健康孕妇50例为对照组,研究组给予门冬胰岛素治疗,比较研究组后和对照组的血糖水平,以及两组胎儿心脏功能的变化情况。结果研究组治疗后的血糖水平相比对照组P> 0.05,研究组子代与对照组子代的LVEDD、LVESD、IVST、LVPWT、LVEF、EF、Tei指数并无明显差异(P> 0.05)。结论门冬胰岛素对妊娠期糖尿病患者的降糖效果显著,能有效稳定子代的心脏功能与结构,值得临床推荐使用。     

过氧化物酶体增殖物受体对肿瘤能量代谢调控的研究进展

过氧化物酶体增殖物受体（PPARs）是细胞能量代谢的主要调节因子,PPARs的3种亚型在多种肿瘤细胞中具有不同的转录活性与效应,能量代谢稳态对细胞的命运至关重要,关于肿瘤的能量代谢一直是热点问题。所有细胞活动都强烈依赖于分解代谢和合成代谢途径之间的平衡,破坏能量平衡和微环境,将表现出一系列的代谢改变包括葡萄糖消耗增加,线粒体呼吸的减少,细胞死亡抗性增强,所有这些都是癌症进展的原因。了解癌症中的代谢过程和阐明PPARs的调控机制会产生新的治疗策略。     

Glucagon and a glucagon-GLP-1 dual-agonist increases cardiac performance with different metabolic effects in insulin-resistant hearts

BACKGROUND AND PURPOSE

The prevalence of heart disease continues to rise, particularly in subjects with insulin resistance (IR), and improved therapies for these patients is an important challenge. In this study we evaluated cardiac function and energy metabolism in IR JCR:LA-cp rat hearts before and after treatment with an inotropic compound (glucagon), a glucagon-like peptide-1 (GLP-1) receptor agonist (ZP131) or a glucagon-GLP-1 dual-agonist (ZP2495).

EXPERIMENTAL APPROACH

Hearts from IR and lean JCR:LA rats were isolated and perfused in the working heart mode for measurement of cardiac function and metabolism before and after addition of vehicle, glucagon, ZP131 or ZP2495. Subsequently, cardiac levels of nucleotides and short-chain CoA esters were measured by HPLC.

KEY RESULTS

Hearts from IR rats showed decreased rates of glycolysis and glucose oxidation, plus increased palmitate oxidation rates, although cardiac function and energy state (measured by ATP/AMP ratios) was normal compared with control rats. Glucagon increased glucose oxidation and glycolytic rates in control and IR hearts, but the increase was not enough to avoid AMP and ADP accumulation in IR hearts. ZP131 had no significant metabolic or functional effects in either IR or control hearts. In contrast, ZP2495 increased glucose oxidation and glycolytic rates in IR hearts to a similar extent to that of glucagon but with no concomitant accumulation of AMP or ADP.

CONCLUSION AND IMPLICATIONS

Whereas glucagon compromised the energetic state of IR hearts, glucagon-GLP-1 dual-agonist ZP2495 appeared to preserve it. Therefore, a glucagon-GLP-1 dual-agonist may be beneficial compared with glucagon alone in the treatment of severe heart failure or cardiogenic shock in subjects with IR.     

Cardiac energetics: sense and nonsense

1. The background to current ideas in cardiac energetics is outlined and, in the genomic era, the need is stressed for detailed knowledge of mouse heart mechanics and energetics. 2. The mouse heart is clearly different to the rat in terms of its excitation-contraction (EC) coupling and the common assumption that heart rate difference between mice and humans will account for the eightfold difference in myocardial oxygen consumption is wrong, because the energy per beat of the mouse heart is approximately one-third that of the human heart. 3. In vivo evidence suggests that there may well be an eightfold species difference in the non-beating metabolism of mice and human hearts. It is speculated that the magnitude of basal metabolism in the heart is regulatable and that, in the absence of perfusion, it falls to approximately one-quarter of its in vivo rate and that in clinical conditions, such as hibernation, it probably decreases; its magnitude may be controlled by the endothelium. 4. The active energy balance sheet is briefly discussed and it is suggested that the activation heat accounts for 20-25% of the active energy per beat and cross-bridge turnover accounts for the balance. It is argued that force, not shortening, is the major determinant of cardiac energy usage. 5. The outcome of recent cardiac modelling with variants of the Huxley and Hill/Eisenberg models is described. It has been necessary to invoke 'loose coupling' to replicate the low cardiac energy flux measured at low afterloads (medium to high velocities of shortening). 6. Lastly, some of the unexplained or 'nonsense' energetic data are outlined and eight unsolved problems in cardiac energetics are discussed.     

PPARs as therapeutic targets in cardiovascular disease

Importance of the field: The role of peroxisome proliferator-activated receptors PPARα, PPARδ and PPARγ in cardiovascular disease is receiving widespread attention. As ligand-activated nuclear receptors, they play a role in regulation of lipid and glucose metabolism. This feature of the PPARs has been successfully exploited to treat systemic metabolic diseases, like hyperlipidemia and type-2 diabetes. Indirectly, their lipid lowering effect also leads to a reduction of the risk for cardiovascular diseases, primarily atherosclerosis.

Areas covered in this review: The pleiotropic effects of each of the PPAR isotypes on vascular and cardiac disease are discussed, with special emphasis on the molecular mechanism of action and on preclinical observations. The mechanism underlying the beneficial effect of PPARs is not confined to whole body metabolism, but also includes modulation of other vital processes, such as inflammation and cell fate (proliferation, differentiation, apoptosis).

What the reader will gain: A large body of preclinical studies indicates that, in addition to their effect on atherogenesis, PPAR ligands also impact on ischemic heart disease and the development of cardiac failure. It remains to be established to what extent these intriguing observations can be translated into clinical practice.

Take home message: The versatile mechanism of action extends the potential therapeutic profile of the PPARs enormously. Conversely, this versatility makes it harder to attain a specific therapeutic effect, without increasing the risk of undesirable side effects. The future challenge will be to design PPAR-based therapeutic strategies that minimize the detrimental side effects.     

PPARs激动剂在心脑血管疾病中的研究进展

PPARs是一类由配体激活的转录因子,属于Ⅱ型核受体超家族成员。PPARs被激活后,能够改善胰岛素抵抗(IR)、纠正脂质代谢紊乱、逆转心肌肥厚、抑制血管平滑肌细胞(VSMCs)和内皮细胞的增殖与迁移,从而改善心脑血管的病理性重构,并具有降压效应。因此,PPARs激动剂的研究在心脑血管疾病的防治中具有重要的理论意义和临床应用价值。本文对近几年的PPARs激动剂进行综述。     

羟苯氨酮对离体鼠心停灌-复灌损伤的保护作用

目的研究羟苯氨酮对全心停灌-复灌损伤的影响。方法采用离体大鼠心脏停灌40 min-复灌30 min模型，从心脏功能、心肌能量代谢、抗氧化、线粒体钙超载及超微结构等方面观察药物作用。结果停灌前和复灌时给予羟苯氨酮(1~10 μmol·L^-1)明显增加复灌时心肌收缩力与冠脉流量，降低冠脉流出液的肌酸磷酸激酶(CPK)活性，对抗损伤所致的心肌三磷酸腺苷(ATP)与磷酸肌酸(PCr)含量降低，增强心肌抗氧化能力，对抗线粒体钙超载，使线粒体超微结构保持得比较完整。结论羟苯氨酮明显对抗停灌-复灌致心肌损伤，为该药保护再灌注损伤提出有力依据。     

Pyruvate dehydrogenase as a therapeutic target for obesity cardiomyopathy

Introduction: Obesity cardiomyopathy is a major public health problem with few specific therapeutic options. Abnormal cardiac substrate metabolism with reduced pyruvate dehydrogenase (PDH) activity is associated with energetic and functional cardiac impairment and may be a therapeutic target.

Areas covered: This review summarizes the changes to cardiac substrate and high energy phosphorus metabolism that occur in obesity and describes the links between abnormal metabolism and impairment of cardiac function. The available evidence for the currently available pharmacological options for selective metabolic therapy in obesity cardiomyopathy is reviewed.

Expert opinion: Pharmacological restoration of PDH activity is in general associated with favourable effects upon cardiac substrate metabolism and function in both animal models and small scale human studies, supporting a potential role as a therapeutic target.     

PPARδ的结构及其生物学功能与疾病

PPARδ是过氧化物酶体增殖激活受体PPAR的一个亚型,主要控制脂肪组织和骨骼肌细胞的脂类代谢和能量解偶联,并参与许多疾病的发生和发展过程。PPARδ作为治疗靶标,它的合成激动剂有望开发成为治疗皮肤损伤和代谢综合症的有效药物。