间歇运动对心梗大鼠梗死周边区单个心肌细胞钙瞬变和收缩功能的影响

目的:探讨间歇运动对心梗大鼠缺血心肌细胞钙瞬变和收缩功能改变的影响。方法:3月龄SD雄性大鼠24只,适应性喂养1周后随机分为假手术组(S)、心梗组(MI)、心梗+运动组(ME),每组8只。MI组结扎左冠状动脉前降支制备心梗模型;S组只穿线不结扎;ME组术后一周开始间歇训练,运动方式为1周适应性运动(10 m/min×30 min/d),然后先以10 m/min×10 min,再以15 m/min×6 min和25 m/min×4 min依次交替运功,60 min/d,每周5 d连续8周。训练结束后次日,腹腔麻醉并分离心肌细胞。采用单细胞可视化动缘探测系统(IonOptix)测定[Ca^2+]i amplitude、[Ca^2]+i荧光比率(Ratio)、Departure velocity、TTP、TTP50%、TTB50%、Return velocity以及Ratio amplitude等钙瞬变指标和±dl/dtmax、SL、PTA、SL shortening%等心肌细胞收缩指标。结果:与S组相比,MI组[Ca^2+]i amplitude、[Ca^2+]i Ratio amplitude,Departure velocity和Return velocity均显著下降(P<0.01),TTB50%、TTP和TTP50%均显著增加(P<0.01),心肌细胞肌节SL Shortening%、PTA、±dl/dtmax均显著减少(P<0.01);与MI组相比,ME组Ratio amplitude、[Ca^2+]i amplitude、Return velocity和Departure velocity均显著提高(P<0.01),TTB50%、TTP和TTP50%均显著缩短(P<0.01,P<0.05),心肌细胞肌节SL Shortening%、PTA、±dl/dtmax均显著提高(P<0.01,P<0.05)。结论:间歇运动可同步改善MI大鼠梗死周边区心肌活细胞的钙瞬变异常和心肌细胞的收缩功能。     

Effects of ghrelin on Cx43 regulation and electrical remodeling after myocardial infarction in rats

Ghrelin is a novel growth hormone-releasing peptide, which has been shown to exert beneficial effects on ventricular remodeling. In this study, we investigated whether ghrelin could decrease vulnerability to ventricular arrhythmias in rats with myocardial infarction and the possible mechanism. Twenty-four hours after ligation of the anterior descending artery, adult male Sprague-Dawley rats were randomized to ghrelin (100 μg/kg) and saline (control group) for 4 weeks. Sham animals underwent thoracotomy and pericardiotomy, but not LAD ligation. Myocardial endothelin-1 (ET-1) levels were significantly elevated in saline-treated rats at the border zone compared with sham-operated rats. Myocardial connexin43 (Cx43) expression at the border zone was significantly decreased in saline-treated infarcted rats compared with sham-operated rats. Ghrelin significantly decreased the inducibility of ventricular tachyarrhythmias compared with control group. Arrhythmias sores during programmed stimulation in saline-treated rats were significantly higher than scores in those treated with ghrelin. The electrophysiological improvement of fatal ventricular tachyarrhythmias was accompanied with increased immunofluorescence-stained Cx43, myocardial Cx43 protein and mRNA levels in ghrelin treated rats. We also shown that ghrelin significantly decreased tissue ET-1 levels at the infarcted border zone. Thus, ghrelin showed the protective effect on ventricular arrhythmias after myocardial infarction. Although the precise mechanism by which ghrelin modulates the dephosphorylation of Cx43 remains unknown, it is most likely that the ghrelin increased expression of Cx43 through the inhibition of ET-1.     

Role of matricellular proteins in cardiac tissue remodeling after myocardial infarction

After onset of myocardial infarction (MI), the left ventricle (LV) undergoes a continuum of molecular, cellular, and extracellular responses that result in LV wall thinning, dilatation, and dysfunction. These dynamic changes in LV shape, size, and function are termed cardiac remodeling. If the cardiac healing after MI does not proceed properly, it could lead to cardiac rupture or maladaptive cardiac remodeling, such as further LV dilatation and dysfunction, and ultimately death. Although the precise molecular mechanisms in this cardiac healing process have not been fully elucidated, this process is strictly coordinated by the interaction of cells with their surrounding extracellular matrix (ECM) proteins. The components of ECM include basic structural proteins such as collagen, elastin and specialized proteins such as fibronectin, proteoglycans and matricellular proteins. Matricellular proteins are a class of non-structural and secreted proteins that probably exert regulatory functions through direct binding to cell surface receptors, other matrix proteins, and soluble extracellular factors such as growth factors and cytokines. This small group of proteins, which includes osteopontin, thrombospondin-1/2, tenascin, periostin, and secreted protein, acidic and rich in cysteine, shows a low level of expression in normal adult tissue, but is markedly upregulated during wound healing and tissue remodeling, including MI. In this review, we focus on the regulatory functions of matricellular proteins during cardiac tissue healing and remodeling after MI.     

Changes of collagen metabolism predict the left ventricular remodeling after myocardial infarction

Objectives: To analyze the predictive value of cardiac collagen metabolism “in vivo" in patients with myocardial infarction (MI) treated with percutaneous coronary intervention (PCI). Design: Forty-five patients (age 66 ± 8.27) underwent biochemical analysis for cardiac collagen metabolism (groups A, B and C); 30 patients with their first MI were treated with successful PCI (group A; n = 30), group B (n = 5) were MI patients with unsuccessful PCI. Group C were patients without MI (n = 10), they underwent elective diagnostic coronary angiography only. The collagen metabolism was analyzed in acute and subacute MI phases by using serum blood markers: the carboxy-terminal propeptide of type I procollagen (PICP), amino-terminal propeptide of type III procollagen (PIIINP) and carboxy-terminal telopeptide of type I collagen (ICTP). Furthermore, the ejection fraction (EF) and left ventricular end-diastolic volume maximal changes in the course of 6 months were measured by echocardiography. Results: A significant increase of both PICP and PIIINP on day 4 following MI was detected. Furthermore, PICP and PIIINP level assessed on the 30th day was significantly higher in the PCI unsuccessful group versus successful group. PICP level on day 4 above 110 ug/l and PIIINP level above 4 ug/l was significantly often found in the subgroup of patients with the EF improvement less than 10% or worsening and with significant left ventricular dilatation during 6 months follow-up. Cardiac catheterization itself does not affect collagen metabolism. Conclusion: We concluded that collagen metabolism markers enable to study in vivo the MI healing and to predict left ventricular functional and volume changes.     

A role of heparin-binding epidermal growth factor-like growth factor in cardiac remodeling after myocardial infarction

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is known to induce cell growth in various cell types via transactivation of epidermal growth factor receptor (EGFR). To investigate the involvement of HB-EGF and EGFR in cardiac remodeling after myocardial infarction (MI), we examined the expressions of mRNA and protein in rat hearts 6 weeks after MI-induction. Where increased expressions of HB-EGF mRNA and protein were observed, infarcted myocardium was replaced by extracellular matrix and interstitial fibroblasts. EGFR mRNA and protein expression did not show significant changes in sham-operated heart tissues, non-infarcted region, and infarcted region. In vitro study demonstrated that HB-EGF mRNA was expressed mainly in cultured fibroblasts rather than in myocytes. We suggest that the interaction between HB-EGF and EGFR transactivation is closely related to the proliferation of cardiac fibroblasts and cardiac remodeling after MI in an autocrine, paracrine, and juxtacrine manner.     

Time-dependent changes of the susceptibility of cardiac contractile function to hypoxia-reoxygenation after myocardial infarction in rats

In this study we analyzed the susceptibility of contractile function of the myocardium to hypoxia-reoxygenation after infarction. For this purpose, the contractility of isolated papillary muscles from rats was studied at high oxygen tension (pO₂ 80 kPa) and during hypoxia (pO₂ 3 kPa) with subsequent reoxygenation at variable intervals between 15 h and 9 weeks after permanent ligation of the left coronary artery. Hypoxic exposure reduced the contractile performance of the preparations to a similar extent in both groups. Notably, the contractility and, in particular, the relaxation rates recovered more completely from hypoxia in the hypertrophied myocardium of rats with coronary artery ligation than in sham-operated (SO) animals. The recovery of contractile function was improved maximally between 6 and 9 weeks after myocardial infarction (MI). The lower sensitivity of the (post)ischemic myocardium to hypoxia-reoxygenation correlated with enhanced left ventricular glutathione peroxidase (GSH-Px) activity (15 h to 9 weeks post-MI) and 2–3-fold increased expression levels (15 h to 6 weeks post-MI) of the 72 kDa heat shock protein (HSP72) in the papillary muscles. These findings suggest that the greater antioxidant potential and, possibly, stimulation of HSPs contribute to the sustained tolerance of the myocardium to hypoxia-reoxygenation injury after infarction.     

Time course of changes in the expression of DHPR, RyR2, and SERCA2 after myocardial infarction in the rat left ventricle

Postinfarction left ventricular remodeling leads to the functional decline of the left ventricle (LV). Since dihydropyridine receptor (DHPR), ryanodine receptor (RyR₂), and sarco-endoplasmic reticulum (SR) Ca²⁺-ATPase2 (SERCA2a) play a major role in the contractility of the heart, the aim of our study was to evaluate the time course of changes in the expression of these proteins 1 day, 2 weeks and 4 weeks after myocardial infarction (MI). Myocardial infarction was produced by ligation of left anterior descending coronary artery of the rat. Transthoracic echocardiography was performed to characterize structural and functional changes after MI. To evaluate protein mRNA levels and the relative amount of proteins, real-time quantitative RT-PCR and Western blotting were used. LV ejection fraction and fractional shortening decreased significantly during the 4-week follow-up period (P < 0.001). Typical features of LV remodeling after MI were seen, with a decrease in anterior wall thickness (P < 0.001) and dilatation of the LV (P < 0.001). Expression of DHPR and RyR₂ mRNAs decreased and Serca2a mRNA tended to decrease 1 day after MI (P < 0.001, P < 0.01 and P = 0.06, respectively), followed by recovery of the expression during the next 4 weeks. In the infarcted hearts the quantities of SERCA2 proteins in the LV were significantly decreased at the time of 4 weeks. In conclusion, MI was associated with transient decrease in the expression of the DHPR and RyR₂ mRNAs and a reduced quantity of SERCA2 proteins in the LV. Since they have a key role in the contraction of the heart, changes in the expression of these proteins may be important regulators of LV systolic function after MI.