糖尿病心肌病发病机制，靶点和中药治疗

高血糖诱发心肌代谢紊乱,引起心肌肥大和纤维化,使心脏舒张和收缩功能发生异常,诱发心衰,造成糖尿病心肌病。其病理过程可能与心肌中激活NADPH氧化酶、内质网应激、内皮素和活性氧通路等炎症因子有关。本文综述糖尿病心肌病的主要机制,相关靶点及中药治疗,为中药治疗糖尿病提供理论依据。     

糖尿病心肌病相关信号通路的研究进展

糖尿病心肌病是一种独立、特异的心肌病,与糖尿病患者发生心力衰竭和死亡率升高密切相关。其病理表现为心肌肥厚和心肌纤维化,发病机制复杂,可能涉及心肌细胞代谢障碍、心肌微血管病变、自主神经病变、胰岛素抵抗及细胞因子异常等多个方面。本文综述了糖尿病心肌病发病机制中研究较多的几条信号通路,为糖尿病心肌病的治疗提供理论依据。     

糖尿病心肌病相关信号通路的研究进展

糖尿病心肌病是一种独立、特异的心肌病,与糖尿病患者发生心力衰竭和死亡率升高密切相关。高血糖引起的心血管并发症涉及心肌病变和血管病变、心肌细胞结构的改变、信号通路和炎症因子的改变等,导致心肌纤维化、心肌肥厚、心脏肥大、心力衰竭和心律失常。综述了糖尿病心肌病发病机制中研究较多的几条信号通路,探究各信号通路在糖尿病心肌病发生、发展过程中对心脏的保护(损伤)作用的相关研究进展。     

巨噬细胞在糖尿病心肌病发病中的作用

近年来,糖尿病的发病率逐年递增,心血管方面的并发症是其主要死亡原因,在没有明显心肌缺血和高血压的情况下,糖尿病发生心衰的风险也明显增高,这些与糖尿病相关的心肌功能和结构的变化称为糖尿病心肌病(diabetic cardiomyopathy,DCM)。目前有关DCM发病机制的学说众多,而巨噬细胞在其发生发展过程中起到了至关重要的作用:如巨噬细胞的胞葬作用(Efferocytosis)下降、极化的改变等,最终可引起心肌的纤维化和心力衰竭。我们总结了目前DCM中巨噬细胞的参与机制,从而探讨潜在的预防和治疗策略。     

糖尿病心肌病发病机制研究进展

糖尿病心肌病是一种特异性心肌病,发病特点是独立于冠状动脉粥样硬化性心脏病、高血压性心脏病等明确原因的心脏疾病之外的原因。糖尿病心肌病发病机制复杂,研究发现包括胰岛素抵抗、炎症反应、氧化应激、心肌能量代谢障碍、钙稳态失衡、自噬等多种机制参与其中。目前临床上尚无特殊治疗药物能有效改善与逆转其发生发展。对近年来糖尿病心肌病发病机制的研究进展进行了综述。     

精胺对高糖引起的大鼠心肌纤维化的影响及其机制

目的: 观察精胺对糖尿病心肌病(DCM)及高糖处理的心肌成纤维细胞(CFs)的保护作用并探讨其机制。方法: ①动物实验:24 只雄性Wistar大鼠随机分为正常组(Control),糖尿病组(T1D)和精胺组(T1D+Sp),每组8只。采用一次性腹腔注射链脲佐菌素(STZ,60 mg/kg)复制 1 型糖尿病大鼠模型,精胺组在 STZ 注射前两周每天腹腔注射精胺(Sp,5 mg/(kg·d)),随后隔天注射,饲养至 12 周。检测各组大鼠血糖、胰岛素水平、射血分数(EF)和缩短分数(FS),并对大鼠心脏组织进行 Masson 染色和 Sirius red 染色。②细胞实验:出生1～3 d的大鼠心脏提取原代 CFs,随机分为正常组(Control),高糖组(HG)和精胺组(HG+Sp,每组 n=6)。高糖(HG,40 mmol/L)处理 CFs 复制细胞模型,精胺组在高糖处理前给予Sp(5 μmol/L)预处理30 min。CCK8检测细胞活性,ELISA法检测培养基中胶原含量,Western blot 测定细胞周期相关蛋白(PCNA、CyclinD1 及 P27)的表达。结果: 与 Control 组相比,T1D 大鼠血糖显著上升,胰岛素水平和心脏功能降低;染色结果显示心肌胶原含量增加。同时,HG 组细胞活力与培养基中胶原含量明显增加,PCNA、CyclinD1 表达上调,而 P27 表达下调。精胺能减轻上述变化,表现为改善心脏功能,调节细胞周期蛋白表达和减轻心肌纤维化水平。结论: 精胺可减轻糖尿病心肌病心肌纤维化的发生,其机制可能与调节细胞周期有关。     

胰岛素信号损伤对糖尿病心肌病的影响

糖尿病心肌病(diabetic cardiomyopathy,DCM)是糖尿病患者的一种慢性并发症,目前已成为糖尿病患者心力衰竭和死亡的主要原因之一。该病是指糖尿病患者在没有其他心血管疾病如冠状动脉疾病、高血压、瓣膜病和先天性心脏病的情况下发生的心功能障碍,其潜在病因尚不清楚。其特征是早期表现为左心室肥厚和舒张功能受损,晚期呈现心肌纤维化和心肌收缩功能障碍,最终导致心力衰竭。一些致病因素,包括高血糖、脂毒性、肾素-血管紧张素系统激活、氧化应激、线粒体功能紊乱以及机体钙稳态的改变,在以往的研究中均被证明与加剧糖尿病患者心脏的结构和功能改变密切相关,但这些致病因素的起因和彼此之间的联系并不十分明确。尽管这些因素的性质和作用机制各不相同,但归结起来,其实都源于胰岛素信号受损所导致的代谢功能异常,使葡萄糖的氧化机能受损,机体绝对的依赖脂肪酸合成ATP,从而对心肌细胞造成损伤。基于此,本文将对胰岛素信号损伤与糖尿病心肌病发病和进展的关系作一综述,以求为该病的治疗提供有效的理论依据。     

心肌纤维化的信号转导机制及新型抑制剂的研究进展

心肌纤维化(myocardial fibrosis, MF)是心肌重构发生的重要病理过程,能够引起心脏衰竭甚至死亡。心肌组织中成纤维细胞异常增殖并转化为肌成纤维细胞以及心肌细胞外基质代谢紊乱导致沉积是心肌纤维化形成的主要病理基础。心肌纤维化发生的分子机制较复杂,已发现多种信号通路参与了心肌纤维化的发生。该文主要对参与调控心肌纤维化的信号转导机制进行了综述,并对新型信号抑制剂的研究进展进行了小结。     

糖尿病心肌病发病机制的研究进展

糖尿病心肌病（diabetic cardiomyopathy, DCM）是一种特殊类型的心脏疾病，在一定程度上增加了糖尿病患者发生心力衰竭的风险，也是糖尿病患者死亡的主要原因之一。DCM的发病机制涉及多个方面，心肌细胞代谢紊乱（如高血糖和胰岛素抵抗）、心肌炎症和纤维化是DCM发病的基础，这些因素单独或联合作用于DCM的发生和发展。目前临床上尚无根治DCM的有效药物，研究疾病的发病机制在开发靶向治疗药物中具有重要意义。主要对当前DCM发病机制的研究进展展开综述，以期为DCM的早期预防和治疗提供理论基础。     

有氧运动对2型糖尿病心肌纤维化的影响

近年来,糖尿病的发病率呈逐年上升趋势,其中2型糖尿病患者大约占总数的90%以上。糖尿病可并发多种并发症,其中糖尿病心肌病是糖尿病重要并发症之一,其病理表现是心肌肥厚、心肌纤维化,已成为糖尿病患者死亡的主要原因。2型糖尿病的心肌纤维化是心肌间质胶原蛋白的过度降解或产生,导致各型胶原比例失调,心肌细胞间质纤维沉积产生的。本文就影响心肌纤维化的因子进行综述。     

Molecular and cellular basis of the aetiology and management of diabetic cardiomyopathy: a short review

Diabetes mellitus is one of the most common chronic diseases affecting millions of people worldwide. Cardiovascular complication including myocardial infarction is one of the major causes of death in diabetic patients. Diabetes mellitus induces abnormal pathological findings including cell hypertrophy, neuropathy, interstitial fibrosis, myocytolysis and apoptosis and lipid deposits in the heart. In addition, the cytoplasmic organelles of cardiomyocytes including the plasma membrane, mitochondrion and sarcoplasmic reticulum are also impaired in both type I and type II diabetes. Hyperglycaemia is a major aetiological factor in the development of diabetic cardiomyopathy in patients suffering from diabetes. Hyperglycaemia promotes the production of reactive oxygen (ROS) and nitrogen species (RNS). The release of ROS and RNS induces oxidative stress leading to abnormal gene expression, faulty signal transduction and apoptosis of cardiomyocytes. Hyperglycaemia also induces apoptosis by p53 and the activation of the cytochrome c-activated caspase-3 pathway. Stimulation of connective tissue growth factor and the formation of advanced glycation end products in extracellular matrix proteins induces collagen cross-linking and contribute to the fibrosis observed in the interstitium of the heart of diabetic subjects. In terms of signal transduction, defects in intracellular Ca2+ signalling due to alteration of expression and function of proteins that regulate intracellular Ca2+ also occur in diabetes. All of these abnormalities result in gross dysfunction of the heart. Beta-adrenoreceptor antagonists, ACE inhibitors, endothelin-receptor antagonist (Bonestan), adrenomedullin, hormones (insulin, IGF-1) and antioxidants (magniferin, metallothionein, vitamins C and E) reduce interstitial fibrosis and improve cardiac function in diabetic cardiomyopathy.     

Non‐coding RNA involvement in the pathogenesis of diabetic cardiomyopathy

In recent years, the incidence of diabetes has been increasing rapidly, which seriously endangers human health. Diabetic cardiomyopathy, an important cardiovascular complication of diabetes, is characterized by myocardial fibrosis, ventricular remodelling and cardiac dysfunction. It has been documented that mitochondrial dysfunction, oxidative stress, inflammatory response, autophagy, apoptosis, diabetic microangiopathy and myocardial fibrosis are implicated in the pathogenesis of diabetic cardiomyopathy. With the development of molecular biology technology, accumulating evidence demonstrates that non‐coding RNAs (ncRNAs) are critically involved in the molecular mechanisms of diabetic cardiomyopathy. In this review, we summarize the pathological roles of three types of ncRNAs (microRNA, long ncRNA and circular RNA) in the progression of diabetic cardiomyopathy, which may provide valuable insights into the pathogenesis of diabetic cardiovascular complications.     

Molecular and cellular basis of the aetiology and management of diabetic cardiomyopathy: A short review

Diabetes mellitus is one of the most common chronic diseases affecting millions of people worldwide. Cardiovascular complication including myocardial infarction is one of the major causes of death in diabetic patients. Diabetes mellitus induces abnormal pathological findings including cell hypertrophy, neuropathy, interstitial fibrosis, myocytolysis and apoptosis and lipid deposits in the heart. In addition, the cytoplasmic organelles of cardiomyocytes including the plasma membrane, mitochondrion and sarcoplasmic reticulum are also impaired in both type I and type II diabetes. Hyperglycaemia is a major aetiological factor in the development of diabetic cardiomyopathy in patients suffering from diabetes. Hyperglycaemia promotes the production of reactive oxygen (ROS) and nitrogen species (RNS). The release of ROS and RNS induces oxidative stress leading to abnormal gene expression, faulty signal transduction and apoptosis of cardiomyocytes. Hyperglycaemia also induces apoptosis by p53 and the activation of the cytochrome c-activated caspase-3 pathway. Stimulation of connective tissue growth factor and the formation of advanced glycation end products in extracellular matrix proteins induces collagen cross-linking and contribute to the fibrosis observed in the interstitium of the heart of diabetic subjects. In terms of signal transduction, defects in intracellular Ca²⁺ signalling due to alteration of expression and function of proteins that regulate intracellular Ca²⁺ also occur in diabetes. All of these abnormalities result in gross dysfunction of the heart. Beta-adrenoreceptor antagonists, ACE inhibitors, endothelin-receptor antagonist (Bonestan®), adrenomedullin, hormones (insulin, IGF-1) and antioxidants (magniferin, metallothionein, vitamins C and E) reduce interstitial fibrosis and improve cardiac function in diabetic cardiomyopathy. (Mol Cell Biochem 261: 187–191, 2004)     

Platelet-neutrophil conjugate formation is increased in diabetic women with cardiovascular disease

 

Our aim is to summarize and discuss the recent literature linking diabetes mellitus with heart failure, and to address the issue of the optimal treatment for diabetic patients with heart failure.

The studies linking diabetes mellitus (DM) with heart failure (HF)

The prevalence of diabetes mellitus in heart failure populations is close to 20% compared with 4 to 6% in control populations. Epidemiological studies have demonstrated an increased risk of heart failure in diabetics; moreover, in diabetic populations, poor glycemic control has been associated with an increased risk of heart failure. Various mechanisms may link diabetes mellitus to heart failure: firstly, associated comorbidities such as hypertension may play a role; secondly, diabetes accelerates the development of coronary atherosclerosis; thirdly, experimental and clinical studies support the existence of a specific diabetic cardiomyopathy related to microangiopathy, metabolic factors or myocardial fibrosis. Subgroup analyses of randomized trials demonstrate that diabetes is also an important prognostic factor in heart failure. In addition, it has been suggested that the deleterious impact of diabetes may be especially marked in patients with ischemic cardiomyopathy.

Treatment of heart failure in diabetic patients

The knowledge of the diabetic status may help to define the optimal therapeutic strategy for heart failure patients. Cornerstone treatments such as ACE inhibitors or beta-blockers appear to be uniformly beneficial in diabetic and non diabetic populations. However, in ischemic cardiomyopathy, the choice of the revascularization technique may differ according to diabetic status. Finally, clinical studies are needed to determine whether improved metabolic control might favorably influence the outcome of diabetic heart failure patients.     

心肌营养素-1和结缔组织增长因子在糖尿病大鼠心肌中的表达及厄贝沙坦的干预作用

目的通过观察心肌营养素-1（CT—1）mRNA和结缔组织增长因子（CTGF）在糖尿病大鼠心肌中的动态表达以及厄贝沙坦干预的影响,探讨CT—1和CTGF在糖尿病心肌病（DMCM）发病机制中的作用。方法SD雄性大鼠78只,随机分为对照组和糖尿病组。用链脲佐菌素（STZ）一次性腹腔注射建立糖尿病模型后,糖尿病组再为厄贝沙坦治疗组及糖尿病未治疗组。治疗组以厄贝沙坦灌服12周。分别在病程2、4、6、8、10、12周处死各组大鼠。称量体重（BW）、全心重量（HW）、左室重量（LVW）,计算心体比（HW／BW）和左室重量指数（LVWI）。检测心肌CT—1 mRNA和CTGF的表达水平;心肌胶原（Col）和心肌血管紧张素（AngⅡ）含量。观察心肌超微结构病理改变。结果糖尿病组大鼠的HW／BW、LVWI明显高于正常对照组（P〈0．01）,厄贝沙坦治疗组大鼠的HW／BW、LVWI明显低于糖尿病组（P〈0．01）,但仍高于正常对照组（P〈0．01）。厄贝沙坦组心肌细胞变性、坏死程度和范围较糖尿病组明显减轻。糖尿病组大鼠CT—1 mRNA、CTGF表达明显卜调,随病程延长呈升高趋势（P〈0．01）,心肌col、AngⅡ含量较正常对照组明显升高（P〈0．01）。而厄贝沙坦治疗组大鼠的CTI mRNA、CTGF表达与糖尿病组相比较下调（P〈0．01）;心肌Col、AngⅡ含量明显低于糖尿病组（P〈0．05）。糖尿病组大鼠心室CT—1mRNA、CTGF和心室局部Col、AngⅡ含量呈明显正相关。结论糖尿病大鼠心肌CT—1mRNA、CTGF表达上调与心肌肥大、间质纤化密切相关,在糖尿病心肌病的心室重构中起重要作用。厄贝沙坦町减轻糖尿病心肌病的心室重构,其心肌保护作用机制可能与其下调CT—1和CTGF水平有关。     

阿魏酸对糖尿病小鼠心肌病变的影响及其机制

目的：研究阿魏酸对高脂饮食结合小剂量链脲佐菌素（STZ）诱导的2型糖尿病小鼠心肌病变的影响,探讨其可能的作用机制。方法：雄性ICR小鼠20只,高糖高脂饮食连续6周,STZ （30 mg/kg）腹腔注射连续5d后,隔9d测空腹血糖（FBG）,超过11.1 mmol/L视为糖尿病造模成功。将此20只小鼠随机分为模型组、阿魏酸组（200 mg/kg,i.g.）,每组10只;另取10只正常小鼠为对照组;连续给药8周。末次给药后,测定FBG、称体重、全心重和左心室重,计算心脏质量指数（HMI）和左室质量指数（LVMI）;测定超氧化物歧化酶（SOD）活力、丙二醛（MDA）含量;Masson染色观察左心室纤维增生情况;免疫组化法测定心肌组织转化生长因子-β1（TGF-β1）、Ⅲ型胶原蛋白表达。结果：与模型组小鼠比较,阿魏酸组小鼠HMI、LVMI减小（（P<0.01,P<0.05）,心肌组织SOD活力升高、MDA含量下降（P<0.05）;心肌胶原纤维沉积减少,间质纤维化改善;免疫组化显示心肌组织TGF-β1和Ⅲ型胶原蛋白表达减少（P<0.01,P<0.05）。结论：阿魏酸对糖尿病小鼠心肌病变具有保护作用,可能与抗氧化及抑制TGF-β1蛋白表达,减少Ⅲ型胶原蛋白沉积有关。     

Lipotoxicity in obesity and diabetes-related cardiac dysfunction

Patients with type 2 diabetes (T2D) are at increased risk for cardiovascular diseases including diabetic cardiomyopathy, which is ventricular dysfunction independent of underlying coronary artery disease and/or hypertension. With numerous advancements in our ability to detect ventricular dysfunction, as well as the molecular mechanisms contributing to ventricular dysfunction in diabetic patients, it is now appreciated that diabetic cardiomyopathy is becoming more prevalent in our population. In spite of these advancements, we do not have any specific therapies currently approved for treating this condition. As obesity increases the risk for both T2D and cardiovascular disease, it has been postulated that obesity-mediated alterations in myocardial lipid metabolism are critical to the pathophysiology of diabetic cardiomyopathy. Indeed, animal studies have provided strong evidence that alterations in either myocardial fatty acid uptake or fatty acid β-oxidation lead to the accumulation of various lipid intermediates including triacylglycerol, diacylglycerol, ceramide, long-chain acyl CoA, acylcarnitine, and many others that are tightly linked to the progression of ventricular dysfunction. We review herein why lipid intermediates accumulate in the heart during obesity and/or T2D, with a focus on which of these various lipid intermediates may be responsible for cardiac lipotoxicity, and whether findings in animal models are relevant to humans. An improved understanding of how these lipid intermediates accumulate in the heart and how they produce cardiac toxicity may lead to the discovery of novel targets to pursue for the treatment of human diabetic cardiomyopathy. This article is part of a Special Issue entitled: Heart Lipid Metabolism edited by G.D. Lopaschuk.