Review of constructing animal models of depression after myocardial infarction北大核心CSCD

心肌梗死后抑郁(depression after myocardial infarction,DAMI)临床发病率较高,对患者的身心健康造成较大危害,但发病机制尚不清楚。采用能模拟人类DAMI发病原因和生物学反应的动物模型进行基础研究,是探索疾病机制的有效途径。该文将动物选择、模型选择、模型制备、行为学评价等建模过程中存在的问题进行总结和思考,以期为DAMI的模型研究提供参考。     

Pharmacological pre- and post-conditioning with the sphingosine-1-phosphate receptor modulator FTY720 after myocardial ischaemia�Creperfusion

Background and purpose:

Our recent experiments demonstrated that the Sphingosine-1-phosphate (S1P) receptor agonist FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol hydrochloride) improves recovery of function after myocardial ischaemia–reperfusion ex vivo. Therefore, we tested the hypothesis that pharmacological post-conditioning with FTY720 reduces infarct size after myocardial ischaemia–reperfusion in vivo.

Experimental approach:

Myocardial ischaemia was induced in Wistar rats by ligation of the left coronary artery for 45 min. FTY720 (0.5 mg·kg⁻¹) was applied i.p. either once, before reperfusion, or twice, 24 h before myocardial ischaemia and before reperfusion. After 24 h reperfusion, we determined infarct size by triphenyltetrazolium chloride staining and granulocyte infiltration by immunohistochemistry. Tumour necrosis factor-α (TNF)-α concentration was determined by elisa. S1P receptor expression was studied by Western blot. Calcium transients were evaluated in Indo-1-loaded cardiomyocytes.

Key results:

In both groups, FTY720 significantly reduced lymphocyte count in peripheral blood. FTY720 treatment attenuated granulocyte infiltration and TNF-α protein expression in reperfused myocardium. However, both treatment regimens were not able to reduce infarct size. FTY720 increased mortality due to induction of fatal ventricular tachyarrhythmias when administered once before reperfusion, but protected against reperfusion arrhythmias when given 24 h prior to ischaemia. Pretreatment selectively down-regulated S1P₁ receptor expression within the myocardium. S1P receptor agonists did not induce calcium deregulation in cardiomyocytes.

Conclusions and implications:

FTY720 applied during reperfusion did not reduce infarct size but increased mortality during myocardial ischaemia–reperfusion due to induction of arrhythmias. Pretreatment with FTY720 before ischaemia abrogated the deleterious pro-arrhythmic effects without reducing infarct size.     

Effect of losartan and captopril on expression of cardiac angiotensin Ⅱ AT1 receptor mRNA in rats following myocardial infarction

目的：探讨氯沙坦（Ｌｏｓ）和卡托普利（Ｃａｐ）对大鼠心肌梗死后血管紧张素Ⅱ（Ａｎｇ）ＡＴ１受体ｍＲＮＡ表达的影响．方法：２４只梗死大鼠随机分为四组并分别用Ｃａｐ（２ｇ·Ｌ－１加水中饮用）、Ｌｏｓ（１０ｍｇ·ｋｇ－１·ｄ－１和３０ｍｇ·ｋｇ－１·ｄ－１，灌胃）及安慰剂治疗６周，假扎鼠作对照，用地高辛标记的ｃＤＮＡ探针，进行点杂交反应，检测ＡｎｇＡＴ１受体ｍＲＮＡ表达．结果：三个药物治疗组的ＡｎｇＡＴ１受体ｍＲＮＡ表达水平分别与安慰剂组比较，均显著降低（Ｐ＜００１）．三个治疗组之间的ＡｎｇＡＴ１受体ｍＲＮＡ表达水平及分别与假扎组比较，均无显著差异（Ｐ＞００５）．结论：Ｃａｐ和Ｌｏｓ均可逆转大鼠心肌梗死后ＡｎｇＡＴ１受体ｍＲＮＡ表达水平的增高．     

Endocannabinoids as mediators in the heart: a potential target for therapy of remodelling after myocardial infarction?

Endocannabinoid production by platelets and macrophages is increased in circulatory shock. This may be protective of the cardiovascular system as blockade of CB(1) cannabinoid receptors exacerbates endothelial dysfunction in haemorrhagic and endotoxin shock and reduces survival. Now evidence suggests that blockade of CB(1) receptors starting 24 h after myocardial infarction in rats has a deleterious effect on cardiac performance, while use of a nonselective cannabinoid receptor agonist prevents hypotension and reduces endothelial dysfunction, although left ventricular end diastolic pressure is elevated. Cannabinoids and endocannabinoid systems may therefore present useful targets for therapy following myocardial infarction.     

Equal access to treatment? Population-based follow-up of drugs dispensed to patients after acute myocardial infarction in Sweden

Background and Objective The establishment of national guidelines is one approach to creating equity in terms of access to care, and both internationally and in Sweden, guidelines have been developed for coronary heart disease. We have analysed drug treatment in Sweden according to national guidelines after acute myocardial infarction (AMI). The aim was to investigate whether there are differences between population groups according to sex, education, country of birth and diabetes. Methods Information was obtained from the Swedish Prescribed Drug Register on drugs dispensed between July and October 2005 for incident cases of AMI during the period 2003–2004 (n = 28,168). Data on socio-economic and demographic conditions were included. Dispensed drugs after AMI were compared to the recommended drug treatment according to Swedish and European guidelines – acetylsalicylic acid (ASA), β-blockers, lipid-lowering drugs and angiotensin-converting enzyme inhibitors (ACE inhibitors). Results We found that, in general, there were only small differences between the sexes and between educational groups. The greatest differences were found in comparisons between regions of birth. In particular, foreign-born patients resident in Sweden but originally from outside the EU25 countries used fewer drugs than Swedish-born patients. The OR (odds ratio) for ASA was 0.73 [95% confidence interval (CI) 0.63–0.85], for β-blockers, 0.72 (0.63–0.83), for lipid-lowering drugs, 0.75 (0.65–0.86) and for ACE inhibitors, 0.76 (0.67–0.86). Conclusions In general, we found only slight differences – or none at all – between population groups in terms of drug treatment after AMI. Only among immigrants from outside the EU25 countries was there a tendency towards a lesser use of the recommended drugs according to the national guidelines.     

Inhibition of Dectin-1 in mice ameliorates cardiac remodeling by suppressing NF-κB/NLRP3 signaling after myocardial infarction

The myocardial inflammatory response is a consequence of myocardial infarction (MI), which may deteriorate cardiac remodeling and lead to dysfunction in the heart post-MI. Dectin-1 is a c-type lectin, which has been shown to regulate innate immune responses to pathogens. However, the role of Dectin-1 in the heart diseases remains largely unknown. In this study, we aimed to investigate the effects of Dectin-1 on cardiac remodeling post-MI. We found that cardiac Dectin-1 mRNA and protein expressions were significantly elevated in C57BL/6 mice after MI. In vitro, hypoxia induced cardiomyocyte injury in parallel with increased Dectin-1 protein expression. Knockdown of Dectin-1 remarkably attenuated cardiomyocyte death under hypoxia and lipopolysaccharide (LPS) stimulation. In vivo administration of adeno-associated virus serotype 9 mediated silencing of Dectin-1, which significantly decreased cardiac fibrosis, dilatation, and improved cardiac function in the mice post-MI. At the molecular level, downregulation of Dectin-1 dramatically suppressed up-regulation of nuclear factor-κB (NF-κB), nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), and the inflammatory genes involved in fibrogenesis and cardiac remodeling after MI. Furthermore, treatment with BAY11-7082, an inhibitor of NF-κB, repressed the activation of NF-κB, and attenuated LPS induced elevation of NLRP3 and cell death in cardiomyocytes. Collectively, upregulation of Dectin-1 in cardiomyocytes post-MI contributes to cardiac remodeling and cardiac dysfunction at least partially by activating NF-κB and NLRP3. This study identified Dectin-1 as a promising therapeutic target for ischemic heart disease.