Molecular mechanics of cardiac myosin-binding protein C in native thick filaments

The heart's pumping capacity results from highly regulated interactions of actomyosin molecular motors. Mutations in the gene for a potential regulator of these motors, cardiac myosin-binding protein C (cMyBP-C), cause hypertrophic cardiomyopathy. However, cMyBP-C's ability to modulate cardiac contractility is not well understood. Using single-particle fluorescence imaging techniques, transgenic protein expression, proteomics, and modeling, we found that cMyBP-C slowed actomyosin motion generation in native cardiac thick filaments. This mechanical effect was localized to where cMyBP-C resides within the thick filament (i.e., the C-zones) and was modulated by phosphorylation and site-specific proteolytic degradation. These results provide molecular insight into why cMyBP-C should be considered a member of a tripartite complex with actin and myosin that allows fine tuning of cardiac muscle contraction.     

曲美他嗪治疗冠心病心力衰竭近期疗效评价

目的探讨曲美他嗪治疗冠心病心力衰竭的临床疗效．方法根据治疗方案将114例冠心病心力衰竭患者分为两组,57例患者实施常规治疗为对照组,57例患者在常规治疗基础上加用曲美他嗪治疗为观察组,疗程6个月,比较两组患者的临床指标改变情况、治疗效果、药物不良反应情况．结果治疗后,两组患者左室射血分数、心输出量、左室短轴缩短率、6min步行距离、每搏输出量均显著增加,两组患者左室舒张末期内径、左室收缩末期内径、血浆B型钠尿肽均显著减小;观察组患者左室射血分数、心输出量、左室短轴缩短率、6min步行距离、每搏输出量均明显大于对照组;观察组患者左室舒张末期内径、左室收缩末期内径、血浆B型钠尿肽均明显小于对照组;观察组患者治疗总有效率明显高于对照组,差异均具有统计学意义（P〈0．05）;观察组患者药物不良反应发生率高于对照组,但差异无统计学意义（P〉0．05）．结论曲美他嗪是治疗冠心病心力衰竭的有效药物,可明显改善患者的临床指标,提高治愈率,药物不良反应少,且安全性高,值得临床推广使用．     

Transgenic mouse model of stunned myocardium

Stunned myocardium is a syndrome of reversible contractile failure that frequently complicates coronary artery disease. Cardiac excitation is uncoupled from contraction at the level of the myofilaments. Selective proteolysis of the thin filament protein troponin I has been correlated with stunned myocardium. Here, transgenic mice expressing the major degradation product of troponin I (TnI1-193) in the heart were found to develop ventricular dilatation, diminished contractility, and reduced myofilament calcium responsiveness, recapitulating the phenotype of stunned myocardium. Proteolysis of troponin I also occurs in ischemic human cardiac muscle. Thus, troponin I proteolysis underlies the pathogenesis of a common acquired form of heart failure.     

Control of stress-dependent cardiac growth and gene expression by a microRNA

The heart responds to diverse forms of stress by hypertrophic growth accompanied by fibrosis and eventual diminution of contractility, which results from down-regulation of alpha-myosin heavy chain (alphaMHC) and up-regulation of betaMHC, the primary contractile proteins of the heart. We found that a cardiac-specific microRNA (miR-208) encoded by an intron of the alphaMHC gene is required for cardiomyocyte hypertrophy, fibrosis, and expression of betaMHC in response to stress and hypothyroidism. Thus, the alphaMHC gene, in addition to encoding a major cardiac contractile protein, regulates cardiac growth and gene expression in response to stress and hormonal signaling through miR-208.     

Normalization of depressed heart function in rats by ribose

Severe constriction of the abdominal aorta and simultaneous injection of isoproterenol in rats induced depression in heart function and reductions in cardiac adenosine triphosphate and total adenine nucleotides. When ribose was continuously infused for 24 hours, biosynthesis of cardiac adenine nucleotides was stimulated to such an extent that the reductions in adenosine triphosphate and total adenine nucleotides were prevented and left ventricular hemodynamic parameters were normal. These results support the hypothesis that adenosine triphosphate is primarily responsible for depression in myocardial contractility and that ribose is cardioprotective through its pronounced effects on adenine nucleotide metabolism in heart muscle.     

Maintained cardiac pumping in anoxic crucian carp

Like most vertebrates, humans die within minutes when deprived of molecular oxygen (anoxia), in part because of cardiac failure. In contrast, some freshwater turtles can survive anoxia for months at low temperatures, but to do so, they drastically suppress cardiac activity and autonomic cardiovascular control. Although Carassius carassius, the crucian carp, shares this anoxia tolerance, we show that it has a unique ability among vertebrates to retain normal cardiac performance and autonomic cardiovascular regulation for at least 5 days of anoxia. These responses point to an unusual tolerance of a vertebrate heart and autonomic nervous system to prolonged anoxia.     

蒲公英水煎剂对蟾蜍离体心脏活动的影响

采用斯氏蛙心插管法和BL-420S智能生物信号显示与处理系统,研究不同浓度蒲公英水煎剂对蟾蜍离体心脏活动的影响。结果表明:与对照组对比,灌流浓度为0.01、0.03、0.05 g/mL的蒲公英水煎剂使离体蛙心心肌收缩力分别下降了1.06%、7.02%和22.15%,蒲公英水煎剂对离体蛙心心肌收缩力具有单向抑制的作用;灌流浓度为0.01、0.03和0.05 g/mL的蒲公英水煎剂对离体蛙心的心率均无显著影响。因此,适当浓度的蒲公英水煎剂可作为临床上减少心输出量和降低血压的中药,另外,也可提取蒲公英中的某些成分制成成药。     

除草剂精克草星胁迫对牛蛙心脏功能和血红细胞的影响

以不同浓度除草剂精克草星溶液(0.0001、0.0005、0.001、0.005、0.01g·L-1和0.05g·L-1)为目标毒物,以牛蛙为研究对象,通过蛙心灌流和生物机能采集系统,研究了精克草星胁迫对牛蛙离体心脏收缩频率和收缩力、外周血红细胞数和红细胞微核率的影响。结果表明,除草剂精克草星对牛蛙离体心脏收缩力和收缩频率均有较大的影响,而且随着除草剂浓度的增加,其影响幅度也加大,具有一定的剂量效应。较低浓度(≤0.0005g·L-1)的精克草星对牛蛙外周血红细胞数和红细胞微核率影响较小,而在较高浓度(≥0.001g·L-1)的精克草星胁迫下,牛蛙外周血红细胞数和红细胞微核率均出现较大的变化,与对照组相比达到了差异显著水平(P<0.05)或差异极显著水平(P<0.01)。     

Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban

Molecular etiologies of heart failure, an emerging cardiovascular epidemic affecting 4.7 million Americans and costing 17.8 billion health-care dollars annually, remain poorly understood. Here we report that an inherited human dilated cardiomyopathy with refractory congestive heart failure is caused by a dominant Arg --> Cys missense mutation at residue 9 (R9C) in phospholamban (PLN), a transmembrane phosphoprotein that inhibits the cardiac sarcoplasmic reticular Ca2+-adenosine triphosphatase (SERCA2a) pump. Transgenic PLN(R9C) mice recapitulated human heart failure with premature death. Cellular and biochemical studies revealed that, unlike wild-type PLN, PLN(R9C) did not directly inhibit SERCA2a. Rather, PLN(R9C) trapped protein kinase A (PKA), which blocked PKA-mediated phosphorylation of wild-type PLN and in turn delayed decay of calcium transients in myocytes. These results indicate that myocellular calcium dysregulation can initiate human heart failure-a finding that may lead to therapeutic opportunities.     

BRADYKININ: VASCULAR RELAXANT, CARDIAC STIMULANT

Bradykinin infusion causes an increase in cardiac output in rats whether the autonomic nervous system is blocked or not. After autonomic blockade, bradykinin causes a lesser decrease in the total peripheral resistance but a greater increase in cardiac output, resulting in an elevation of arterial pressure. The increase in cardiac output is caused by a small increase in heart rate and a substantial increase in stroke volume. The fact that these increases are observed after autonomic blockade suggests that bradykinin increases cardiac output by direct stimulation of the heart.     

Control of myocardial contraction: the sensitivity of cardiac actomyosin to calcium ion

The control by calcium ion of the adenosine triphosphatase activity of cardiac actomyosin is similar to that of white skeletal actomyosin. This finding indicates that the slower contraction and relaxation of heart muscle do not reflect different levels to which free calcium ion concentration around the myofibrils must be adjusted during contraction and relaxation and suggests a mechanism whereby myocardial contractility may be regulated.     

Transient regenerative potential of the neonatal mouse heart

Certain fish and amphibians retain a robust capacity for cardiac regeneration throughout life, but the same is not true of the adult mammalian heart. Whether the capacity for cardiac regeneration is absent in mammals or whether it exists and is switched off early after birth has been unclear. We found that the hearts of 1-day-old neonatal mice can regenerate after partial surgical resection, but this capacity is lost by 7 days of age. This regenerative response in 1-day-old mice was characterized by cardiomyocyte proliferation with minimal hypertrophy or fibrosis, thereby distinguishing it from repair processes. Genetic fate mapping indicated that the majority of cardiomyocytes within the regenerated tissue originated from preexisting cardiomyocytes. Echocardiography performed 2 months after surgery revealed that the regenerated ventricular apex had normal systolic function. Thus, for a brief period after birth, the mammalian heart appears to have the capacity to regenerate.     

Atrial natriuretic peptide elevation in congestive heart failure in the human

A sensitive radioimmunoassay for atrial natriuretic peptide was used to examine the relation between circulating atrial natriuretic peptide and cardiac filling pressure in normal human subjects, in patients with cardiovascular disease and normal cardiac filling pressure, and in patients with cardiovascular disease and elevated cardiac filling pressure with and without congestive heart failure. The present studies establish a normal range for atrial natriuretic peptide in normal human subjects. These studies also establish that elevated cardiac filling pressure is associated with increased circulating concentrations of atrial natriuretic peptide and that congestive heart failure is not characterized by a deficiency in atrial natriuretic peptide, but with its elevation.     

Progress in Study of Cardiac Muscle Tissue Engineering

各种类型的心脏疾病一直是困扰人类的一个难题,目前临床上采用的各种治疗方法虽然能够缓解心脏病的症状,但均无法根治。心肌组织工程的研究有望使这一难题获得解决。心肌组织工程研究主要包括种子细胞获取、支架材料研制以及工程化心肌组织构建等方面内容。在此,从心肌组织工程研究的基本途径、工程化心肌组织的特点、移植存在的问题及可能的解决办法等几方面,对近年来心肌组织工程的研究作一概述。     

对慢性心衰心阳虚证及其微观指标关系的思考

本文通过对慢性心力衰竭心阳虚证症候特点、病程变化机制、血流动力学、心功能分级、心脏负荷标志物、神经内分泌相关激素、炎症反应物等相关指标的关联整理,研究其诊断价值,为病证结合慢性心力衰竭心阳虚证提供辅助诊断依据,并对心衰心阳虚证微观辨证发展现状进行反思。     

Myosin: a link between streptococci and heart

Murine monoclonal antibodies to Streptococcus pyogenes reacted with skeletal muscle myosin. High molecular weight proteins in extracts of human heart tissue that reacted with an antibody to S. pyogenes also reacted with a monoclonal antibody to ventricular myosin. Adsorption of the antibody to streptococci with S. pyogenes simultaneously removed reactivity of the antibody for either S. pyogenes or myosin. These results indicate that myosin shares immunodeterminants with a component of S. pyogenes.     

Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2

Ventricular arrhythmias can cause sudden cardiac death (SCD) in patients with normal hearts and in those with underlying disease such as heart failure. In animals with heart failure and in patients with inherited forms of exercise-induced SCD, depletion of the channel-stabilizing protein calstabin2 (FKBP12.6) from the ryanodine receptor-calcium release channel (RyR2) complex causes an intracellular Ca2+ leak that can trigger fatal cardiac arrhythmias. A derivative of 1,4-benzothiazepine (JTV519) increased the affinity of calstabin2 for RyR2, which stabilized the closed state of RyR2 and prevented the Ca2+ leak that triggers arrhythmias. Thus, enhancing the binding of calstabin2 to RyR2 may be a therapeutic strategy for common ventricular arrhythmias.     

Wnt5a control of cell polarity and directional movement by polarized redistribution of adhesion receptors

Mechanisms by which Wnt pathways integrate the organization of receptors, organelles, and cytoskeletal proteins to confer cell polarity and directional cell movement are incompletely understood. We show that acute responses to Wnt5a involve recruitment of actin, myosin IIB, Frizzled 3, and melanoma cell adhesion molecule into an intracellular structure in a melanoma cell line. In the presence of a chemokine gradient, this Wnt-mediated receptor-actin-myosin polarity (W-RAMP) structure accumulates asymmetrically at the cell periphery, where it triggers membrane contractility and nuclear movement in the direction of membrane retraction. The process requires endosome trafficking, is associated with multivesicular bodies, and is regulated by Wnt5a through the small guanosine triphosphatases Rab4 and RhoB. Thus, cell-autonomous mechanisms allow Wnt5a to control cell orientation, polarity, and directional movement in response to positional cues from chemokine gradients.     

Regulation of chamber-specific gene expression in the developing heart by Irx4

The vertebrate heart consists of two types of chambers, the atria and the ventricles, which differ in their contractile and electrophysiological properties. Little is known of the molecular mechanisms by which these chambers are specified during embryogenesis. Here a chicken iroquois-related homeobox gene, Irx4, was identified that has a ventricle-restricted expression pattern at all stages of heart development. Irx4 protein was shown to regulate the chamber-specific expression of myosin isoforms by activating the expression of the ventricle myosin heavy chain-1 (VMHC1) and suppressing the expression of the atrial myosin heavy chain-1 (AMHC1) in the ventricles. Thus, Irx4 may play a critical role in establishing chamber-specific gene expression in the developing heart.