Calcium homeostasis behavior and cardiac function on left ventricular remodeling by pressure overload

Sarcoplasmic reticulum Ca²⁺-ATPase (SERCA2a) and sarcolemmal Na⁺/Ca²⁺ exchanger (NCX1) structures are involved in heart cell Ca²⁺ homeostasis. Previous studies have shown discrepancies in their function and expression in heart failure. The goal of this study was to evaluate heart function and hypertrophied muscle Ca²⁺-handling protein behavior under pressure overload. Twenty male Wistar rats were divided into two groups: Aortic stenosis (AoS), induced by a clip placed at the beginning of the aorta, and Control (Sham). After 18 weeks, heart function and structure were evaluated by echocardiogram. Myocardial function was analyzed by isolated papillary muscle (IPM) at basal condition and Ca²⁺ protein functions were evaluated after post-pause contraction and blockage with cyclopiazonic acid in IPM. Ca²⁺-handling protein expression was studied by western blot (WB). Echocardiogram showed that AoS caused concentric hypertrophy with enhanced ejection fraction and diastolic dysfunction inferred by dilated left atrium and increased relative wall thickness. IPM study showed developed tension was the same in both groups. AoS showed increased stiffness revealed by enhanced resting tension, and changes in Ca²⁺ homeostasis shown by calcium elevation and SERCA2a blockage maneuvers. WB revealed decreased NCX1, SERCA2a, and phosphorylated phospholambam (PLB) on serine-16 in AoS. AoS had left ventricular hypertrophy and diastolic dysfunction compared to Sham; this could be related to our findings regarding calcium homeostasis behavior: deficit in NCX1, SERCA2a, and phosphorylated PLB on serine-16.     

不同年龄小鼠缺血性心力衰竭后心室重塑程度的比较

 目的：研究不同年龄小鼠缺血性心衰后心室重塑程度的变化。方法：选择3月龄和18月龄的雄性C57BL/6J小鼠共100只,每个月龄组50只,在2组中分别随机选取 40只,结扎左冠状动脉定量控制心梗面积,建立稳定缺血性心衰模型,每组其余10只作为假手术组,于术后8周行心脏超声评价各组心功能变化;称量全心脏及左心室重量并计算左心室质量指数(LVMI);免疫组化检测心肌Ⅰ、Ⅲ型胶原表达,Masson染色检测心肌纤维化的程度并计算心肌间质胶原分数(CVF)。结果：与低龄组相比,老龄组心脏破裂率（18% vs 10%）和心力衰竭死亡率（22% vs 10%）均高于低龄组(P＜0.05);老龄组心室腔明显增大,心率较快,左室短轴收缩功能障碍更明显（P＜0.05）;老龄组LVMI明显增加（P＜0.05）;老龄组CVF、Ⅰ型胶原的表达以及Ⅰ/Ⅲ型胶原的比值显著高于低龄组（P＜0.05）。结论：老龄小鼠缺血性心衰后心肌胶原分布异常,心室重塑程度更重,心功能降低更明显。     

Superoxide-dependent cathepsin activation is associated with hypertensive myocardial remodeling and represents a target for angiotensin II type 1 receptor blocker treatment

The elastolytic activity of cathepsins in the myocardium is implicated in hypertensive heart failure (HF). Given that reactive oxygen species are also implicated in protease activation associated with cardiac remodeling, we examined the role of the reactive oxygen species-induced cathepsin activation system in cardiac remodeling during the development of hypertensive HF. Dahl salt-sensitive hypertensive rats maintained on a high-salt diet were treated with vehicle, the cathepsin inhibitor E64d, or the angiotensin receptor blocker olmesartan from 12 to 19 weeks of age. Cathepsin expression and activity were increased in the left ventricle of HF rats; olmesartan inhibited these effects, restored the balance between elastin and collagen in the left ventricle, and suppressed degradation of the elastic lamina of coronary arteries of HF rats. Furthermore, olmesartan inhibited up-regulation of NADPH oxidase subunits and activity as well as superoxide generation. These effects of olmesartan were mimicked by E64d and were accompanied by amelioration of cardiac fibrosis. Finally, olmesartan and apocynin reduced angiotensin II-induced increases in cathepsin mRNA and protein levels in cultured rat neonatal cardiac myocytes. These data suggest that cathepsins likely trigger and promote cardiac remodeling and that blocking the angiotensin II type 1 receptor attenuates cathepsin expression and activity by inhibiting the production of superoxide by NADPH oxidase, thereby attenuating cardiac remodeling and dysfunction.     

rAAV1-SERCA2a转染改善心力衰竭犬心功能及其机制探讨

 目的:研究重组1型腺相关病毒(rAAV1)介导的肌浆/内质网Ca2+-ATP酶2a（SERCA2a）基因转移对心力衰竭（HF）犬心功能的作用并探讨其机制。方法:采用快速右心室起搏建立比格犬的HF模型，设对照组、HF组、HF+EGFP组和HF+SERCA2a组（均n＝4）。后2组经开胸心肌内注射rAAV1-EGFP或rAAV1-SERCA2a，剂量为1×1012病毒基因组。结果:基因转移30 d后，HF+SERCA2a组超声心动图左室射血分数接近对照组，较HF组明显改善（P＜0.05)，SERCA2a mRNA较HF组显著提高（P＜0.05），SERCA2a蛋白在心肌组织中的表达显著高于HF组（P＜0.05)，心肌细胞凋亡指数和基质金属蛋白酶9（MMP-9）表达较HF组显著降低（P＜0.05）。HF+EGFP组各项观察指标接近HF组。但是，受磷蛋白mRNA的水平没有改变。结论:rAAV1-SERCA2a转染上调HF犬心肌组织SERCA2a的表达，能改善心功能，抑制心室重塑；其机制可能与抑制心肌细胞凋亡、下调MMP-9表达有关。     

海沙瑞林对慢性心力衰竭大鼠心交感神经重构的影响*

目的：探讨海沙瑞林对慢性心力衰竭（ CHF）大鼠心交感神经重构的影响。 方法： SD大鼠随机分为对照 组（ Control 组）、假手术组（ Sham组）、心力衰竭组（ HF组）和海沙瑞林干预组（ HF+Hx 组），应用冠状动脉结 扎法制作CHF大鼠模型，HF+Hx 组大鼠连续4 周尾静脉注射海沙瑞林 100 μg·kg-1·d-1，其他3 组注射等量的生 理盐水。超声心动图测量左心室功能；H-E 染色及Masson 染色观察各组大鼠心肌病理结构变化；免疫组织化学和 免疫印迹检测脑钠肽（ BNP）、神经生长因子（ NGF）、酪氨酸羟化酶（TH）和生长相关蛋白43（ GAP43）表达。 结果：海沙瑞林干预升高CHF大鼠左室射血分数，改善左心室功能，减轻HF组心肌损伤结构病理改变，降低心 肌细胞内BNP 表达，增加NGF、TH和GAP43 表达，差异均具有统计学意义。 结论：CHF大鼠存在心交感神经重构， 海沙瑞林通过改变心交感神经重构， 改善心功能和CHF的预后可能是其实现心保护的机制之一。     

心脏收缩力调节对慢性心力衰竭兔心室肌电重构的影响

目的:观察心脏收缩力调节(cardiac contractility modulation, CCM)对慢性心力衰竭兔心室肌电重构的影响并探讨其可能的机制。方法:30只新西兰大白兔随机分为3组:假手术组、心衰组(采用升主动脉根部套扎法建立兔慢性心力衰竭模型)和心衰+CCM刺激组(模型制作成功后给予4周的CCM治疗)。电生理记录仪测定QTc和心室有效不应期(ventricular effective refrective period, VERP);采用RT-qPCR和Western blot检测心室肌Kv1.4、Kv4.3和缝隙连接蛋白43 (connexin 43, Cx43)的mRNA和蛋白的表达水平。结果:(1)实验第12周末,心衰兔QTc显著延长(P<0.05);实验第16周末,与心衰组相比,心衰+CCM组经4周CCM刺激后QTc显著缩短(P<0.05)。实验第16周末,与假手术组相比,心衰组、心衰+CCM组VERP显著延长(P<0.05);与心衰组相比,CCM可缩短心衰模型兔的VERP(P<0.05)。(2)与假手术组相比,心衰组心肌组织中Kv1.4、...     

β3肾上腺素能受体激动剂和抑制剂对心衰大鼠心室MMP2和9表达的影响

 目的 研究β3肾上腺素能受体(AR)激动剂和抑制剂对心衰(HF)大鼠左室基质金属蛋白酶2、9(MMP-2、MMP-9)表达的影响,明确β3AR在左室重构中的作用。方法 Wistar大鼠140只,随机分为对照组10只,余130只制备HF模型,选取心衰大鼠随机分为HF组(n=11)、激动剂组(n=12)、抑制剂组(n=10)。激动剂组、抑制剂组分别给予BRL37344 1.65?g/kg、SR59230A 50?g/kg尾静脉注射,2次/周。分别于4和8周时各组选取5只大鼠测定以下指标：心功能的相关指标、左室重量/体质量、心肌胶原容积分数、MMP-2、MMP-9蛋白和mRNA表达。结果 与对照组比较,HF组大鼠心功能明显下降,激动剂组随时间增加心功能恶化较HF组更明显,而抑制剂组心功能明显改善;与对照组比较,HF组MMP-2、MMP-9 mRNA、蛋白表达增高;激动剂组增加更明显; 拮抗剂组表达减少(均为P＜0.01)。结论 β3AR抑制剂改善心功能可能通过抑制心肌MMP-2、MMP-9表达来实现。     

Myocardial remodeling and bioelectric changes in tachycardia-induced heart failure in dogs

In this study, electrical and structural remodeling of ventricles was examined in tachycardia-induced heart failure (HF). We studied two groups of weight-matched adult male mongrel dogs: a sham-operated control group (n=5) and a pacing group (n=5) that underwent ventricular pacing at 230 bpm for 3 weeks. Clinical symptoms of congestive HF were observed in both groups. Their hemodynamic parameters were determined and the severity of the HF was evaluated by M-mode echocardiography. Changes in heart morphology were observed by scanning electron and light microscopy. Ventricular action potential duration (APD), as well as the 50 and 90% APD were measured in both groups. All dogs exhibited clinical symptoms of congestive HF after rapid right ventricular pacing for 3 weeks. These data indicate that rapid, right ventricular pacing produces a useful experimental model of low-output HF in dogs, characterized by biventricular pump dysfunction, biventricular cardiac dilation, and non-ischemic impairment of left ventricular contractility. Electrical and structural myocardial remodeling play an essential role in congestive HF progression, and should thus be prevented.     

Neural remodeling may partly contribute to the abnormality of excitation-contraction coupling in heart failure

Heart failure (HF) is a major and growing public health problem in the world. About 50% of deaths in HF occur suddenly due to malignant arrhythmia. Therefore, exploring the further mechanisms of chronic HF and finding new therapy targets are essential for the progression of HF treatment. Recently, some published papers suggested that myocardial neural remodeling and abnormal excitation-contraction (EC) coupling might partly contribute to the development of HF and sudden cardiac death. Even though a few studies have demonstrated that the sympathetic nerve system (SNS) may have significant impact on the functional states of myocardial EC coupling through the beta-adrenergic signaling pathway, so far, it still remains unknown that whether neural remodeling affects the EC coupling. Studies from Marks' group demonstrated that 70% of cardiac ryanodine receptors (RyR2), which located on the sarcoplasmic reculum (SR) controlling intracellular Ca(2+) release and muscle contraction in the heart, from failing hearts were abnormal and only 15% exhibited the most severe defects. In addition, Litwin et al. observed that temporal and spatial heterogeneities in local Ca(2+) release events in a rabbit model of HF after myocardial infarction. Because some studies have demonstrated that chronic SNS hyperactivity in HF led to protein kinase A (PKA) hyperphosphorylation of RyR2 in the heart, and the myocardial sympathetic nerve distribution become heterogeneous in the setting of HF. Thus, it is reasonable for us to propose the hypothesis that neural remodeling may partly account for the abnormality of EC coupling in HF.     

黄芪多糖对阿霉素诱导的心力衰竭模型大鼠的保护作用

目的 探讨黄芪多糖对大鼠阿霉素性心衰的保护作用。方法 取雄性SD大鼠30只,随机分为对照组、心衰模型组和黄芪多糖组,每组10只。黄芪多糖组连续14d黄芪多糖水溶液灌胃［3g/(kg·d)］,正常对照组和心衰模型组灌胃等量蒸馏水。心衰模型组和黄芪多糖组分4次静脉注射阿霉素［10.4mg/(kg·2d)］复制心衰模型。给药全部结束后,检测大鼠心肌重构、细胞凋亡和抗氧化性等指标。结果 阿霉素导致心肌纤维化,肌原纤维溶解断裂,线粒体肿胀变性,应用黄芩多糖能明显改善心衰症状。血流动力学和TUNEL染色进一步证实黄芪多糖能缓解阿霉素对心脏的损伤,这一作用可能是通过降低丙二醛(MDA)含量和Bax的表达,同时增加超氧化物歧化酶（SOD）活性和Bcl-2的表达来实现的。结论 黄芪多糖对阿霉素性心衰有较好的保护作用。     

Cardiac molecular markers of programmed cell death are activated in end-stage heart failure patients supported by left ventricular assist device

BackgroundCardiomyocyte apoptosis increases in heart failure (HF) and is implicated in disease progression. The apoptotic cell is not inevitably committed to death, and appropriate therapy like left ventricular assist device (LVAD) support could offer a rescue of cellular functions. Literature data regarding the modulation of the apoptotic process during LVAD support are still controversial.MethodsTo assess whether LVAD implantation modifies the apoptotic profile in the heart, cardiac tissue was collected from end-stage HF patients before LVAD implant (pre-LVAD, n=22) and at LVAD removal (post-LVAD, n=6) and from stable HF patients on medical therapy without prior circulatory support (HTx, n=7) at heart transplantation as control. Caspase (Casp)-3, Bax, Bcl-2, and Hsp72 cardiac mRNA and protein expression were evaluated by real-time polymerase chain reaction and Western blotting (WB) in the three groups of patients. Immunohistochemical analysis, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, and DNA laddering analysis were performed; cellular size and interstitial fibrosis content were also determined.ResultsAll the apoptotic indices were increased in the post-LVAD group compared to pre-LVAD, specially antiapoptotic Hsp72 and proapoptotic Bax (Hsp72: 3.27±0.41 vs. 0.76±0.14, P<.001; Bax: 2.15±0.38 vs. 1.10 ± 0.29, P=.035; post-LVAD vs. pre-LVAD, respectively). The significant increase in Hsp72 was confirmed by WB and immunohistochemical analysis.ConclusionLVAD appears to induce an activation of apoptotic mediators, mainly at the mitochondrial level, while the following activation of Casp-3 is reduced by the significant increase of Hsp72, whose enhancement could be an important factor in cardiac remodeling associated with LVAD support.     

心肌肌浆网Ca2+-ATP酶基因转导改善慢性心力衰竭犬心功能的研究

目的： 探讨以重组腺相关病毒(rAAV)为载体的心肌肌浆网Ca2+-ATP酶(SERCA2a)基因转导对慢性心力衰竭犬心功能的影响。方法: 选取成年比格犬17只，随机分为对照组4只和心力衰竭组11只。快速右心室起搏建立慢性心力衰竭犬模型并随机分为心力衰竭组4只、心力衰竭＋绿色荧光蛋白（EGFP）组4只、心力衰竭＋SERCA2a组5只(其中1只在开胸后死亡)。接受基因导入的心力衰竭犬行开胸术，分别向心肌内注射携带EGFP和SERCA2a基因的rAAV载体。于基因转导30d时停止起搏后进行超声心动图和血流动力学检查。结果: 基因转导30 d时，心力衰竭＋SERCA2a 组犬的症状及超声心动图指标与心力衰竭＋EGFP组相比有显著好转（P<0.05）；与对照组相比无显著差别。血流动力学监测发现，转导SERCA2a的犬LVSP、+dp/dtmax和-dp/dtmax明显升高，平均值较EGFP组分别增加54.12％［(214.72±31.74)mmHg vs (139.32±36.79)mmHg］、146.81％［(6 779.43±217.58)mmHg/s vs (2 746.85±931.23)mmHg/s］和71.52％［(-4 341.42±322.02)mmHg/s vs (-2 531.14±616.15 mmHg/s)］，LVEDP则降低了63.43％［(21.86±6.95)mmHg vs (59.78±6.92)mmHg］，所有参数与对照组相比无显著差异。心力衰竭＋EGFP组犬心肌冰冻切片在激光共聚焦显微镜下可见弥漫绿色荧光。结论: 以rAAV为载体介导SERCA2a基因转导能够改善慢性心力衰竭犬心脏的收缩和舒张功能，是1种有前景的治疗慢性心力衰竭的方法。     

有氧运动抑制心梗后心力衰竭大鼠左室重塑及交感神经重塑

目的:探讨长期有氧运动对心梗后心力衰竭(心衰)大鼠模型左心室及交感神经重塑(结构重塑与功能重塑)的影响,为心衰的机制研究及康复治疗提供科学依据和有效方法。方法:健康雄性Wistar大鼠通过结扎冠状动脉前降支建立心梗后心衰模型,术后4周随机分为假手术安静组(S组)、心衰安静组(H组)和心衰运动组(HE组)。HE组进行10周跑台训练,S组和H组保持安静状态。超声心动术检测心脏结构与功能,即左室舒张期内径(LVIDd)、左室收缩期内径(LVIDs)、左室舒张期前壁厚度(LVAWDd)、左室收缩期前壁厚度(LVAWDs)、左室舒张期后壁厚度(LVPWDd)、左室收缩期后壁厚度(LVPWDs)、缩短分数(FS)和左室射血分数(LVEF);Masson染色进行心脏组织病理学观察并获得心肌胶原容积分数(CVF);高压液相色谱法检测心肌和血浆去甲肾上腺素(NE)水平;经皮下引导电极连续采集心电信号,对自主神经功能参数——心率变异性(HRV)进行频域分析,包括总功率谱(TP)、归一化低频功率谱(LFn)、归一化高频功率谱(HFn)和LF/HF比值;实时荧光定量PCR检测心肌I型胶原(Col-I)、III型胶原(Col-III)、心房钠尿因子(ANF)、α-肌球蛋白重链(α-MHC)、β-肌球蛋白重链(β-MHC)和肌质网Ca2+-ATP酶(SERCA2a)mRNA表达,Western blotting法检测心肌神经生长因子(NGF)及其受体(Trk A)和酪氨酸羟化酶(TH)蛋白表达。结果:(1)与S组比较,H组体重(BW)、LVIDd、FS、LVEF、TP、HFn、α-MHC和SERCA2a的mRNA,NGF、Trk A和TH的蛋白表达降低(P0.05);左室重量(LVW)、左室质量指数(LVMI)、LVAWDd、LVAWDs、LVPWDd、LVPWDs、CVF、血浆和心肌NE含量、LFn、LF/HF、ANF、β-MHC、Col-I和Col-III的mRNA表达升高(P0.05)。(2)与H组比较,HE组LVW、LVMI、LVIDd、FS、LVEF、TP、HFn、α-MHC和SERCA2a的mRNA,NGF、Trk A和TH的蛋白表达升高(P0.05);CVF、血浆和心肌NE含量、LFn、LF/HF、ANF、β-MHC、Col-I和Col-III的mRNA表达降低(P0.05)。结论:长期有氧运动可抑制心梗后心衰大鼠左室重塑与交感神经重塑,心功能和自主调节改善。     

Cardiac autonomic nerve abnormalities in chronic heart failure are associated with presynaptic vagal nerve degeneration

Background: Understanding of the functional and structural disturbances of cardiac autonomic nerves in ventricular hypertrophy and eventual chronic heart failure (CHF) remains unclear. Methods and results: ECG signals were obtained by a radio transmitter from male Wistar rats that received monocrotaline (MCT) via subcutaneous injection. Heart rate (HR) and HR variability (HRV) were analyzed. The RR interval, total power (TP), low frequency (LF) power, high frequency (HF) power, and LF/HF (L/H) power ratio were measured. Ultrastructural changes in cardiac autonomic nerves at the sinoatrial (SA) node region were studied using an electron microscope. TP and HF powers in MCT-induced right ventricular hypertrophy (RVH) and eventual CHF were significantly decreased, and HR was significantly increased at week 5 or later after the MCT injection. The electron microscopic findings indicated the depletion of neurotransmitter vesicles and degradation of parasympathetic but not sympathetic nerve endings in the SA node region of the heart. Conclusion: MCT-induced RVH and CHF rats showed presynaptic vagal nerve degradation prior to sympathetic nerve derangement in the heart.     

The pathophysiology of myocardial infarction-induced heart failure

Heart failure (HF) is a multifactorial disorder and is usually the end stage of many cardiovascular diseases (CVD). HF presents one of the highest morbidity and mortality indices worldwide and high costs to public health organizations. Myocardial infarction (MI) is the most prevalent CVD in the Western world and leads to HF when its management is inadequate. It has a destructive potential for heart cells and abruptly reduces the cardiac output, a clinical condition known as heart dysfunction that might progress to HF. Many acute and chronic adaptations occur due to MI that progress to HF, e.g., neurohumoral hyperactivity, inflammatory response and cardiac remodeling. Herein, we reviewed in simplistic manner the processes involved in setting of MI until the establishment of HF.     

美托洛尔对心力衰竭大鼠心肌细胞磷酸化缝隙连接蛋白43表达及心肌细胞凋亡的影响

 目的：观察美托洛尔对心力衰竭（HF）大鼠在体心肌组织磷酸化缝隙连接蛋白43（p-Cx43）表达水平和心肌细胞凋亡的影响,并探讨其可能机制。方法：SD大鼠100只随机分为5组（n=20）：假手术（sham）组、HF组、小剂量（1.25 mg·kg-1·d-1）美托洛尔治疗（MetoA）组、中剂量（5 mg·kg-1·d-1）美托洛尔治疗（MetoB）组和大剂量（20 mg·kg-1·d-1）美托洛尔治疗（MetoC）组。缩窄腹主动脉建立HF动物模型,术后第4周开始给药至第8周。术后第4周和第8周超声心动图测定血流动力学指标;术后第8周取出心脏,HE和Masson染色观察心脏结构改变和胶原纤维增生情况,Western blotting检测p-Cx43表达水平,TUNEL法检测心肌细胞凋亡,p-Cx43表达水平与心肌细胞凋亡指数进行Pearson相关分析。结果：(1) 美托洛尔治疗改善HF大鼠血流动力学,在治疗剂量范围内美托洛尔剂量增加可有效逆转HF时的心肌重塑,呈剂量依赖效应。(2) HF组中p-Cx43表达量显著高于sham组（P<001）,而随美托洛尔治疗剂量的增加,p-Cx43表达量较HF组逐渐降低,各治疗组间两两比较亦有显著差异（P<001）。(3) HF组心肌细胞凋亡指数［(51.17±6.94)%］较sham组［(4.62±1.60)%］明显增加（P<001）;MetoA组凋亡指数为(40.60±4.15)%, MetoB组凋亡指数为(30.66±4.00)%,MetoC组凋亡指数为(22.24±5.69)%,均显著低于HF组（P<001）,各治疗组间两两比较亦有显著差异（P<001）。(4) 大鼠心肌组织p-Cx43表达水平与心肌细胞凋亡指数呈显著正相关（r=0.905, P<001）。结论: 美托洛尔对抗HF诱导的心肌细胞凋亡的机制可能与其抑制p-Cx43表达有关。     

Involvement of endoplasmic reticulum stress-associated apoptosis in a heart failure model induced by chronic myocardial ischemia

Apoptosis plays a critical role in the pathogenesis of chronic myocardial ischemia (CMI) and heart failure (HF). Endoplasmic reticulum stress (ERS) is one of the newly defined signaling pathways which initiate apoptosis. Previous studies have shown that ERS-associated apoptosis is involved in the pathogenesis of HF induced by pressure-overload and acute myocardial infarction. Also, in?vitro experiments have proved that ischemia is a strong stimulus of ERS. This study aimed to demonstrate whether ERS-associated apoptosis is involved in the pathogenesis of CMI-induced HF. We established a HF model induced by CMI in mini pigs via placement of an ameroid constrictor around the proximal anterior descending branch of the left coronary artery (LAD). Furthermore, we used myocardial perfusion imaging, echocardiographic and hemodynamic measurements, hematoxylin-eosin staining, and terminal deoxynucleotidyl transferase-mediated DNA nick-end labeling staining to identify the existence of myocardial ischemia and cardiac dysfunction and of enhanced apoptosis in the ischemic heart. We performed immunohistochemistry, Western blot, and real-time PCR to analyze the hallmark of ERS glucose-regulated protein 78 (GRP78). The ERS-associated apoptotic pathways, CCAAT/enhancer-binding protein homologous protein (CHOP), caspase-12, and c-Jun NH2-terminal kinase?1 (JNK1) were also examined. We found that all three of these pathways were activated and that GRP78 protein and mRNA levels were significantly enhanced in the myocardium of HF mini pigs induced by CMI. These results suggest that ERS is present in the CMI-induced HF pig model, and that ERS-associated apoptosis is involved in the pathophysiology of HF induced by CMI.     

Decreased responsiveness of vascular postjunctional alpha1-, alpha2-adrenoceptors and neuropeptide Y1 receptors in rats with heart failure.

Heart failure is associated with increased sympathetic nerve activity. We hypothesized that chronic sympathetic stimulation in heart failure resulted in decreased vascular sympathetic responsiveness. A pithed rat model was employed to evaluate peripheral vascular alpha-adrenoceptor and neuropeptide Y (NPY) receptor responsiveness. Heart failure was induced in Sprague-Dawley rats by coronary artery ligation. Sham operated rats (Sham) served as controls. Two months after this surgical procedure, both heart failure (n = 30) and Sham (n = 30) rats underwent standard pithing procedure. Pressor responses to preganglionic sympathetic nerve stimulation (PNS) and activation of postjunctional alpha1- and alpha2-adrenoceptors as well as Y1 receptors were studied. In response to PNS, cardiac index was similar between heart failure and sham rats (P = n.s.). Mean arterial pressure (MAP) increased in a frequency-dependent fashion after PNS in heart failure rats as well as in control rats. All the agonists used, i.e. the alpha1-adrenoceptor agonist phenylephrine, the alpha2-adrenoceptor agonists clonidine and BHT933 as well as NPY, induced dose-dependent increases in MAP in heart failure and in sham rats. However, in rats with heart failure, the response to all the agonists studied was significantly decreased and the dose response curves were shifted to the right (P < 0.01). We conclude that in vivo vascular response to postjunctional alpha1- and alpha2-adrenoceptors as well as Y1 receptors are decreased in rats with heart failure.