CN116966176A - 脂肪酸结合蛋白4抑制剂在治疗射血分数保留型心力衰竭中的应用 - Google Patents
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Abstract
本发明涉及脂肪酸结合蛋白4抑制剂在治疗射血分数保留型心力衰竭中的应用。所述的应用具体为:通过口服给药的方式施用脂肪酸结合蛋白4(FABP4)抑制剂BMS309403,对射血分数保留型心力衰竭进行预防和/或治疗。
Description
技术领域
本发明属于生物医药技术领域,具体而言,涉及脂肪酸结合蛋白4抑制剂在治疗射血分数保留型心力衰竭中的应用。
背景技术
射血分数保留型心力衰竭(HFpEF)是指左心室射血分数(LVEF)≥50%的心力衰竭,其特点是舒张功能障碍和射血分数的保留。HFpEF占所有心力衰竭病例的一半,并与多种合并症有关,包括糖尿病、高血压和限制性心肌病。在HFpEF中,慢性全身性炎症和代谢紊乱不仅影响心肌,还影响其他器官,如肾脏、肺和骨骼肌等。在所有心力衰竭(HF)中,HFpEF占至少50%。HFpEF的5年生存率只有35%。HFpEF的病理生理机制复杂,一直是心力衰竭中的治疗难点。
迄今为止,HFpEF的病理生理机制尚不完全清楚,对于降低HFpEF患者的发病率和死亡率尚无特异性的治疗方法,探索其他治疗HFpEF的药物十分必要。
目前,针对HFpEF的药物治疗常用药物主要包括β受体阻滞剂、血管紧张素转换酶抑制剂(ACEI)或血管紧张素受体/脑啡肽酶抑制剂(ARNI)、盐皮质激素受体拮抗剂(MRA)等有效治疗射血分数降低型心力衰竭(HFrEF)的药物。其中,
(1)β受体阻滞剂可以有效降低患者的心率,但是在一部分舒张功能不全患者中使用β受体阻滞剂治疗并进行研究,发现患者BNP水平较高,且出现了非预期的心衰症状恶化。虽然降低心率对防止心房颤动患者心室率过高,预防快速性心律失常,及治疗心绞痛症状有益,但其对长期疗效的影响并不确定。
(2)ACEI可减少血管紧张素Ⅱ的生成,抑制血管紧张素转化酶,使血管紧张素Ⅱ的生成减少,并减少醛固酮分泌,使水钠潴留减轻。ARNI具有血管紧张素受体阻断和利钠肽系统激活的双重作用,具有排钠、利尿减轻容量负荷和抗心肌纤维化的作用,然而在其治疗HFpEF的临床研究中,ACEI/ARNI并没有显著减少HFPEF患者的死亡和心衰总住院的复合终点。
(3)MRA药物在HFrEF中具有明确的作用,但在HFpEF中效果较差,可能是因为随着LVEF的增加,RAAS的病理生理作用不够显著。
2022ESC心衰指南和2022AHA/ACC/HFSA指南提出,HFpEF患者根据需要使用利尿剂等缓解症状,并将钠-葡萄糖协同转运蛋白2抑制剂(SGLT2i)作为2a级推荐。在EMPEROR-PRESERVED试验中,SGLT2i恩格列净降低了LVEF>40%的HF患者复合CV死亡或HF总住院的风险。在SOLOIST-WHF(索格列净对2型糖尿病患者心力衰竭恶化的影响)试验中,SGLT2和SGLT1双重抑制剂索格列净减少了糖尿病患者和HF恶化(HFrEF和HFpEF)的CV死亡和HF住院的主要终点。达格列净DELIVER研究也进一步阐释SGLT2i使HFpEF的患者获益。但在这些临床试验中,纳入的患者中只有部分患者射血分数≥50%,且随着LVEF的升高,药物降低死亡率的作用减弱,可见SGLT2i只对部分HFpEF患者有效。因此,探索更为安全有效的能够缓解HFpEF的药物至关重要。
基于此,提出本发明。
发明内容
本发明首先涉及脂肪酸结合蛋白4(FABP4)抑制剂BMS309403在制备治疗和/或预防射血分数保留型心力衰竭的药物和/或药物组合物中的应用。
进一步的,所述的药物为:经胃肠消化道道给药的药物、经静脉注射给药的药物、经皮下包埋给药方式给药的药物,优选为经胃肠消化道给药的药物。
进一步的,所述的药物和/或药物组合物中包含,治疗有效量的BMS309403,以及必要的药用辅料。
本发明的有益效果在于,
脂肪酸结合蛋白(FABPs)家族在脂肪细胞中表达较多的是脂肪酸结合蛋白4(FABP4)。FABP4是一种脂质结合蛋白,不仅参与脂质转运,而且调节葡萄糖和脂质稳态。临床研究表明在心力衰竭患者的血清中,FABP4表达升高。BMS309403又称选择性FABP4抑制剂,它能够竞争性地抑制内源性游离脂肪酸与FABP4的脂肪酸结合囊泡的结合。
而在本发明中,通过使用动物模型探究HFpEF的病理机制,发现脂肪酸结合蛋白4(FABP4)抑制剂BMS309403,能够显著缓解HFpEF的相关症状。
附图说明
图1、FABP4抑制剂(BMS309403)对小鼠的射血分数保留型心力衰竭模型的治疗效果。
图1A、BMS309403治疗后,HFpEF小鼠的体重显著下降;
图1B、BMS309403治疗后,HFpEF小鼠的心脏重量与胫骨长度的比值(HW/TL)显著降低至接近正常值;
图1C、BMS309403治疗后,HFpEF小鼠的瘦体重(去脂体重)明显改善;
图1D、BMS309403治疗后,HFpEF小鼠的脂肪含量的比例明显改善;
图1E、心脏超声结果显示,Control组、HFpEF组、BMS309403治疗组三组小鼠的射血分数(LVEF)均处于正常水平;
图1F、与HFpEF组相比,BMS309403治疗组小鼠舒张功能明显恢复(E/e’显著降低);
图1G、BMS309403治疗后,HFpEF小鼠收缩压(SBP)显著下降;
图1H、BMS309403治疗后,HFpEF小鼠葡萄糖耐量障碍明显改善。
图2、BMS309403化合物结构式。
图3、模型小鼠治疗前后的心脏脂肪组织病理染色(HE染色)结果图。
图3A、Control组;
图3B、HFpEF组;
图3C、BMS309403治疗组;
图3D、定量结果。
具体实施方式
生化试剂及试剂盒
表1、生化试剂及试剂盒名称及供应商
实验仪器设备
表2、实验仪器设备名称及供应商
实验动物
雄性野生型小鼠(C57BL/6J)均购自北京华阜康生物科技股份有限公司。所有动物均在北京市心肺血管疾病研究所SPF级环境动物房进行饲养繁殖。野生小鼠需为达到10-12周龄,体重在25-30g左右的雄性小鼠。所有实验操作均根据NIH与1996年制定的《实验动物管理及使用指南》和首都医科大学实验动物管理部门规定的实验流程进行。所有实验动物按照随机方法进行分组。
动物表型检测
脉搏式尾套法血压测量
使用脉搏式尾套法无创血压测量系统(上海奥尔科特生物科技有限公司,中国),小鼠在标准化动物房内,打开脉搏式尾套测压系统,完成定标后,将小鼠放进测压专用笼,在恒温毯(37℃)上放置5~10min,待小鼠状态稳定后,通过尾部脉搏感受器感受小鼠尾部脉搏,待脉搏稳定后,开始测压。在测量过程中,可根据小鼠状态适当调整恒温毯温度和测压次数,并记录BP值。最后通过仪器读取BP值(≥6次),去掉最高值和最低值,取平均值作为该小鼠的最后BP值。
腹腔注射葡萄糖耐量实验
小鼠空腹12h后,通过腹腔注射葡萄糖(2g/kg溶于无菌水)进行葡萄糖耐量试验。在注射前和注射后15、30、60、90、120分钟,通过尾静脉取血法用血糖仪测定血糖水平(mmol/L)。
小动物超声
在HFpEF模型构建的第0、10周和给药5周后,使用小动物超声仪Vevo2100高分辨率成像仪器(Vevo2100;Visual Sonics)进行心脏超声数据采集。过程为:首先使用异氟烷气体(10%)麻醉小鼠,之后置于超声金属板上,采用5%的异氟烷维持麻醉状态,使用脱毛膏祛除小鼠胸部毛发,上面涂耦合剂,使用超声探头采集小鼠心脏左室流出道M超,通过心室水平的短轴M超模式扫描获取LVEF和其他收缩功能指标;使用脉冲波和组织多普勒成像在二尖瓣水平测量舒张功能,获得麻醉小鼠的心尖四腔视图,在控制体温的条件下采集超声心动图,将异氟烷降至1.0-1.5%,并进行调整以保持心率在400-500次/min范围内。之后通过分析软件计算左心室舒张末期内径(LVDd)、左心室收缩末期内径(LVDs)、舒张末期室间隔厚度(IVSd)、左心室舒张末期后壁厚度(LVPWd)、左心室短轴缩短分数(FS)、左室射血分数(LVEF)、舒张早期通过二尖瓣的峰值血流速度(E波)、舒张晚期心房收缩引起的峰值血流速度(A波)、等容舒张时间(IVRT)、二尖瓣环舒张早期心肌舒张速度峰值(E’波)和充盈早期减速时间(EDT)。所有参数均至少测量3次,并给出平均值。
实施例1、射血分数保留型心力衰竭模型(HFpEF“two-hit”小鼠模型)的构建
将8周-12周的雄性C57BL/6J小鼠随机分为两组,置于动物室饲喂,维持12小时的光/暗循环,可以自由获得食物和水。
一组为对照组(n=12):给予普通饮食。
一组为HFpEF组(n=24):给予高脂饮食(D12492),将L-NAME以0.5g/L浓度溶于饮水中。
对构建HFpEF模型的表型评价方案为:
1.在喂养第0、10周时,对两组小鼠进行体重测量。
2.在喂养第0、10周时,对两组小鼠进行小动物心脏超声,测量心脏射血分数情况及左心室舒张功能障碍程度等心功能情况。
3.在喂养第0、10周时,对两组小鼠进行脉搏式尾套法血压测量,测量血压变化情况。
4.在喂养第0、10周时,对两组小鼠进行腹腔注射葡萄糖耐量实验,测量糖耐受情况。
在喂养第10周时,可以观察到:
①HFpEF组体重较对照组明显增加,呈现肥胖状态;
②HFpEF组左室射血分数≥50%,即存在射血分数保留;HFpEF组E/e’≥40,说明存在左室舒张功能障碍;
③HFpEF组收缩压≥130mmHg,即存在高血压;④HFpEF组较对照组出现葡萄糖不耐受。以上说明模型构建成功。
实施例2、给予FABP4抑制剂(BMS309403)对射血分数保留型心力衰竭的治疗效果
脂肪酸结合蛋白(FABP4)抑制剂BMS309403订购来自Abmole Bioscience(中国),货号是M6265。
使用如实施例1构建成功的HFpEF小鼠模型,将上述持续喂养10周的HFpEF组小鼠随机分为两组,
(1)HFpEF组(n=8):继续喂高脂饮食(D12492),将L-NAME以0.5g/L浓度溶于饮水中。
(2)BMS309403治疗组(n=8):继续喂高脂饮食(D12492),将L-NAME以0.5g/L浓度溶于饮水中,同时将BMS309403拌于高脂饮食饲料中以15mg/kg/d剂量口服给药。
持续5周后检测治疗效果。
给药观察指标包括:
1.给药5周后,对小鼠进行小动物体成分分析,测量总体重、瘦体重(去脂体重)、脂肪含量变化情况。
2.给药5周后,对小鼠进行小动物心脏超声,测量心脏射血分数情况、左心室舒张功能障碍程度等心功能情况。
3.给药5周后,对小鼠进行脉搏式尾套法血压测量,测量血压变化情况。
4.给药5周后,对小鼠进行腹腔注射葡萄糖耐量实验,测量糖耐受情况。
观察终点:
给药5周后,收集所有小鼠心脏,称取心脏重量并测量小鼠胫骨长度,收取白色脂肪组织做病理染色(HE染色)测脂肪细胞大小变化。
检测指标中,总体重分成脂肪和非脂肪两种成分。前者称为脂体重(或称肥体重),后者称为瘦体重(或称去脂体重),本实验检测瘦体重指标。
结果显示,BMS309403治疗后HFpEF小鼠的典型表型显著改善,具体为:
(1)用BMS309403治疗5周后的HFpEF小鼠体重显著下降(图1A);
(2)心脏重量与胫骨长度的比值(HW/TL)显著降低至接近正常值(图1B);
(3)瘦体重(去脂体重)和脂肪含量的比例明显改善(图1C、D);
(4)心脏超声结果显示,Control组、HFpEF组、BMS309403治疗组三组小鼠的射血分数(LVEF)均处于正常水平(图1E),与HFpEF组相比,BMS309403治疗组小鼠舒张功能明显恢复(E/e’显著降低),接近正常(图1F),同时还观察到,BMS309403治疗后小鼠收缩压(SBP)显著下降(图1G);
(5)葡萄糖耐量障碍明显改善,恢复正常(图1H)。
(6)脂肪HE染色(200倍镜下)显示BMS309403治疗后脂肪细胞大小明显减小(图3A-D,其中A为Control组,B为HFpEF组,C为BMS309403治疗组,D为定量结果)。
综上可见,口服BMS309403可以显著改善HFpEF模型的临床症状。
最后需要说明的是,以上实施例仅用作帮助本领域技术人员理解本发明技术方案的实质,不用于限定本发明的保护范围。
Claims (3)
1.脂肪酸结合蛋白4(FABP4)抑制剂BMS309403在制备治疗和/或预防射血分数保留型心力衰竭的药物和/或药物组合物中的应用。
2.根据权利要求1所述的应用,其特征在于,所述的药物为:经胃肠消化道道给药的药物、经静脉注射给药的药物、经皮下包埋给药方式给药的药物,优选为经胃肠消化道给药的药物。
3.根据权利要求1或2所述的应用,其特征在于,所述的药物和/或药物组合物中包含,治疗有效量的BMS309403,必要的药用辅料。
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