肥厚型心肌病(hypertrophic cardiomyopathy,HCM)是猫最常见的心脏病,其典型特征为左心室室壁增厚,导致左心室肥大,该病影响10%~15%的宠物猫种群[1-2]。大约23%的HCM患猫在5年之内因心脏病死亡, 在突然死亡的心脏病猫中,常见心肌纤维化病理,该病理变化被认为是导致猫心因性猝死的重要风险因素[3-5]。据报道,HCM在老年猫尤其高发,其中原发性HCM概率可高达29%[6]。目前认为猫的HCM多为非遗传性,虽然已证实部分猫品种高发HCM[7-12],但迄今为止,只有在缅因猫与布偶猫等少数猫品种中证实了与MYBPC3基因突变相关的遗传性HCM[13]。大多数HCM猫发病原因仍不明确。内分泌疾病、高血压、脱水、炎症、肿瘤等疾病都可能引起猫左心室肥厚[14]。大部分HCM患猫处于亚临床状态,但是一旦疾病发展到终末期,HCM患猫可能出现充血性心力衰竭(congestive heart failure,CHF)、动脉血栓栓塞(arterial thromboembolism,ATE),甚至猝死。目前临床上常用的HCM检查方法包括超声心动图、胸部X线检查以及心脏生物标志物检测,其中超声心动图是诊断猫HCM的金标准。对于大部分平均体型的猫来说,在M型超声或者2D超声扫查的超声心动图上,舒张期末期左心室壁厚 < 5 mm被认为是正常,≥6 mm则提示为肥厚。对于左心室壁厚在5~6 mm之间的猫,应结合其体型、家族病史、左心房和左心室的形态及功能进行定量评估[15]。在病理学上,HCM猫的心肌有3个主要特征:左心室明显增厚、心肌细胞紊乱和纤维化。大多数猫表现为室间隔和左心室游离壁的向心性增厚,导致左心室腔缩小,同时伴有心肌纤维排列紊乱,心肌细胞以垂直和倾斜的角度排列、冠状动脉壁异常增厚和心肌纤维化[16]。
目前,用于治疗猫HCM的药物很少,并且大多是对症治疗。如心衰时常用髓袢利尿药药物呋塞米、血管紧张素转换酶抑制剂贝那普利[17-18];预防ATE常用抗血小板药物氯吡格雷、阿司匹林[19-20]等。新型的肌节蛋白抑制剂——马瓦卡坦(mavacamten)MYK-461及其替代物MYK-581具有治疗猫HCM的潜力,其作用机制是抑制肌节力从而降低收缩力,减少左心室流出道阻塞,改善心室舒张功能[21-23]。然而该药物虽然目前在猫HCM模型上表现出有改善心室舒张作用[24],但其在临床上对猫HCM的治疗效果与安全性评价尚缺乏有力的循证医学证据。而对于猫的心肌纤维化问题,目前尚无针对性的治疗药物,鉴于心肌纤维化的临床重要性,新型抗纤维化药物亟需开发。
2 HCM猫的心肌纤维化特点心肌纤维化是由于细胞外基质(extracellular matrix,ECM)合成增多、降解不足从而引起的ECM蛋白过度沉积,可导致心脏功能障碍和心电异常[25]。心肌纤维化是猫HCM的标志,临床上,心肌纤维化的猫可能出现室性心动过速、左心室功能障碍、心力衰竭以及心源性猝死[4]。根据心肌病变过程,心肌纤维化分为两种不同的类型:间质性心肌纤维化和替代性心肌纤维化[26]。间质性心肌纤维化是指在不同因素影响下,以胶原纤维为代表的ECM合成异常增多,并在细胞间或血管周围沉积,该病变通常可逆。而替代性心肌纤维化则是由于心肌细胞损伤坏死后,引起胶原纤维原替代肌细胞,此时病程往往不可逆。在疾病的晚期,心肌间质纤维化也会发展成替代性纤维化[27-28]。
HCM猫心肌纤维化的发展呈动态变化。在亚临床HCM猫的心肌组织中,与正常猫相比,其组织中中性粒细胞和胶原含量增多,出现小动脉壁肥大和不同程度的间质纤维化,心肌纤维排列轻度紊乱,这表明HCM疾病初期的猫的心肌存在炎性变化,并在此过程伴有胶原沉积增加[29]。随着疾病的发展,心肌整体细胞数量减少,心肌间质巨噬细胞增多,心肌细胞排列紊乱,血管周围出现明显的纤维化灶[30-31]。在疾病发展的终末期伴有单核细胞浸润和多灶性大面积心肌纤维化[32],并且出现左心室管腔和左心房扩张,左心室大量纤维组织沉积和病理性壁内冠状动脉数量增加的现象。近期,对猫HCM心肌超微结构变化的研究确定了最终HCM心脏能量耗尽是心肌中线粒体结构发生改变的结果[33-34]。为了更好地了解这一系列复杂的病理变化,探索猫心肌纤维化发病的潜在机制必不可少。
3 心肌纤维化的发病机制关于猫心肌纤维化的发病机制,目前鲜有报道,鉴于猫与人HCM病理变化的相似性[2],在人类医学方向关于心肌纤维化发病机制的研究进展,可作为猫心肌纤维化发病机制的重要参考。心肌损伤后,由于其对损伤的响应,会出现一系列复杂的ECM重塑过程,ECM的过度重塑可造成心肌纤维化,引起心脏的几何形状和力学性能的改变,最终发生心衰。目前已知心肌纤维化的形成与肾素-血管紧张素-醛固酮系统(renin-angiotensin-aldosterone system, RAAS)过度激活、细胞因子调控、ECM调节失衡以及microRNA的调控有关。
负责调节机体体液平衡的RAAS是心肌纤维化研究的经典对象。在该系统中,肾素水解血管紧张素原释放血管紧张素Ⅰ(angiotensin Ⅰ,AngⅠ),而血管紧张素转换酶(angiotensin coverting enzyme, ACE)可以将AngI转化为血管紧张素Ⅱ(angiotensin Ⅱ,AngⅡ)以及促进醛固酮的分泌, 从而引起心肌纤维化。AngⅡ可以作用于血管紧张素1型受体(angiotensin Ⅱ type 1 receptor,AT1R),通过络氨酸激酶的途径使细胞外信号调节激酶激活,然而大量的AT1R可导致细胞肥大、血管收缩、炎性细胞因子释放,使心肌成纤维细胞合成大量的纤连蛋白和胶原蛋白,进而以旁分泌或自分泌的方式发挥促纤维化作用。血管紧张素2型受体(angiotensin Ⅱ type 2 receptor,AT2R)则是可释放缓激肽从而减轻氧化应激、抗炎及抗纤维化。过量的AngⅡ和醛固酮通过调节心脏中的细胞因子和趋化因子的表达引起炎症和心血管重塑。AngⅡ可以通过心肌细胞和心肌成纤维细胞诱导转化生长因子β(transforming growth factor beta, TGF-β)的转录和蛋白表达从而刺激胶原蛋白合成,并结合心肌成纤维细胞膜上的高亲和力Ⅰ型受体,使Ⅲ型胶原水平升高,导致ECM沉积和胶原含量增加,从而引发心肌纤维化[35-42]。
已有研究表明, TGF-β是由一类结构及功能相关的多肽生长因子组成,最初在免疫系统的网络调节中发现,其有多个亚型,如TGF-β1、TGF-β2和TGF-β3[43]。由于在正常心脏组织中,TGF-β1调节多种不同类型细胞的信号传导和功能,因此最常作为心肌纤维化发生发展的研究靶点[44-45]。激活的TGF-β1主要通过与TGFβ受体Ⅱ(TGFβ receptor type-2, TβRⅡ)的结合导致Ⅰ型受体ALK5和Ⅰ型受体ALK1的磷酸化,进而激活典型通路Smad2/3、Smad1/5/8途径,以及非典型通路,包括ERK、JNK、p38MAPK、PI3K/Akt及其下游靶基因的表达。磷酸化后的信号分子具有生物学活性, 能够促进Ⅰ型和Ⅲ型胶原蛋白合成和沉积、增强成纤维细胞的活力, 进而导致心肌纤维化或心肌重塑的发生[43, 46-50]。在发生轻度和重度心肌纤维化的猫中, TGF-β2和TGF-β3在心肌细胞的表达水平升高,伴有Ⅰ型和Ⅲ型胶原的沉积,而TGF-β1未见明显变化[51]。目前TGF-β在猫心肌纤维化中的作用尚不明确,具体机制还有待深究。最新的一项关于猫HCM发病机制的研究指出,HCM猫心肌中促炎因子与包括TGF-β在内的促纤维化因子显著增多,先前研究已证实,随着年龄的增长,猫心肌由促炎因子高表达状态转为促纤维化因子高表达。在猫HCM疾病发展的初期,心肌中有大量炎症因子的存在,如IL-1、IL-2、IL-4、IL-6、IL-18、IFN-γ、TNF-α[52]。这些炎症因子也参与心肌修复,代偿性心室肥厚和心肌调节以改变血流动力学。心肌损伤初期发生炎症反应可能有益,但一直处在炎症状态下易导致心肌进一步损伤和纤维化,此时心肌由促炎状态转变为高表达TGF-β以及ECM重塑酶的促纤维化状态[30, 53-57]。
在正常的ECM中,心肌间质的胶原蛋白可以保持心的形态和功能,主要的胶原成分是Ⅰ型和Ⅲ型胶原蛋白,Ⅰ型约占80%,Ⅲ型约占12%。而基质金属蛋白酶(matrix metalloproteinases,MMPs)及其组织抑制剂(tissue inhibitors of metalloproteinases,TIMPs)可以互相调节从而降解胶原蛋白,维持ECM的稳定。当心脏受到损伤时,主要由活化的成纤维细胞——肌成纤维细胞介导ECM重塑。心脏损伤初期,炎性细胞和介质聚集在损伤区域,诱导成纤维细胞激活分化为肌成纤维细胞。具有高度收缩性的α-平滑肌肌动蛋白通过特殊的细胞表面结构与ECM连接,重塑周围的ECM。当成纤维细胞过度激活时可导致MMPs与TIMPs产生与代谢失调,引起ECM蛋白的过度沉积而造成心肌纤维化[58-61]。在正常的猫心脏中,心肌细胞表达TIMP-3、TIMP-2;正常的心肌成纤维细胞表达MMP-2、MMP-3、MMP-9、MMP-13、MMP-14和TIMP-1。而在发生轻度和重度心肌纤维化的猫中,MMP-2的表达量增加,但TIMP-2的表达量降低,这可能是MMP2过度降解胶原蛋白的结果[51]。
除了上述描述的机制外,近期有研究发现心肌纤维化与miRNA的调控有关。miRNA是小的非编码的RNA,被称为mRNA表达和蛋白质水平的重要转录后调节因子。人类医学研究发现,miRNA-21可以通过TGF-β/Smads信号通路促进成纤维细胞的增殖与分化以及通过MAPK/ERK、PTEN/MMP-2信号通路抑制成纤维细胞的凋亡从而加重心肌纤维化的发展,而含有micRNA-378的微泡可通过抑制MAPK的磷酸化来减轻心肌纤维化[62]。在一项猫的研究中发现MiR-381-3p和MiR-486-3p在HCM猫血清中显著表达,并且预测在心血管信号通路中调节蛋白磷酸酶2、调节亚基B(PPP2R2C)和miR-320e可能参与了HCM的病理通路,具体机制有待深入研究[63]。血清中的miRNA是各种疾病的潜在生物标志物,因为它们在血清中稳定存在[64]。然而,目前尚不清楚血清中的miRNA在多大程度上反映了特定组织的损伤。
4 猫的抗心肌纤维化药物的发展现状由于RAAS的激活在心血管疾病的发病机制中起着核心作用,阻断RAAS被认为是最有效的心脏保护干预措施之一,通常使用血管紧张素转换酶抑制剂(angiotensin-coverting enzyme inhibitor, ACEI)抑制血管紧张素转化酶活性,减少AngⅡ及醛固酮的合成,从而减少Ⅰ型胶原的合成和沉积,发挥抑制纤维化的作用[65]。然而有研究表明,在兽医临床上常常使用的ACEI贝那普利,虽然患有心脏病的猫对其耐受性良好,但其对猫心脏病的治疗效果有待进一步的研究[18]。AT1R阻断剂替米沙坦是猫高血压的新型治疗药物,研究证据表明,在高血压性左心室肥厚的大鼠模型中,替米沙坦通过抑制心肌的瘦素信号通路,改善心功能以及心肌纤维化重塑[66]。醛固酮受体阻断剂螺内酯是猫CHF时常用的利尿药物之一,在一项关于家族性HCM的缅因猫的研究中,螺内酯改善了左心室的舒张功能,减少左心室肥厚。在心肌肌钙蛋白T转基因大鼠HCM模型中,螺内酯逆转了间质纤维化,减少了50%的心肌细胞紊乱,并在治疗10周内通过二尖瓣流入速度测量评估发现其可以改善心舒张功能[67-68]。托拉塞米是一种与呋塞米相似的强效髓袢利尿剂,可用于猫的CHF治疗。除利尿作用外,托拉塞米还具有抗心肌纤维化的功能,其可以通过纠正赖氨醯胺氧化酶过表达和增强胶原交联的能力从而起到对抗心纤维化的作用[69-70]。
5 猫的抗心肌纤维化药物的未来方向在人类医学领域,抗心肌纤维化药物的相关研究与应用较多,主要是作用于RAAS以及TGF-β1信号通路。除上述提到的ACEI、AT1R阻断剂等针对RAAS的药物外,通过TGF-β1信号通路干预心肌纤维化的药物也有报道。他汀类药物可以通过干预TGF-β1和MMPs信号通路阻止或逆转心肌纤维化的进展,例如,普伐他汀在AngⅡ过表达的小鼠成纤维细胞中表现出抑制MMP-3和MMP-9能力[71];阿托伐他汀可以作用于TGF-β1信号通路从而降低胶原沉积[72];GW788388被鉴定为ALK5和TβRⅡ的有效抑制剂[73],也具有抗心肌纤维化的潜力。Liu等[74]在小鼠模型中研究表明,富含亮氨酸的α-2糖蛋白1(leucine-rich α-2 glycoprotein 1, LRG1)可以通过与TGF-β1竞争TβRⅡ结合来抑制心肌成纤维细胞的活化,而PPARβ/δ和TGF-β1可以通过SMRT共同调节LRG1的表达,起到抑制纤维化的作用,并且发现血清LRG1水平的升高与心室功能不全和心衰密切相关。这一结果在猫的血清研究中得以证明,与健康猫相比,CHF猫血清中的LRG1显著增加,表明LRG1可能与CHF猫的心脏重塑相关[75]。
近年来,miRNA、干细胞、外泌体以及中医药物等也是抗心肌纤维化新药研发的热点,未来也可能成为对抗猫心肌纤维化药物研发的方向[76-78]。无论如何,治疗心肌纤维化都是通过调节其病理生理学机制从而达到治疗或逆转的效果,目前在猫关于心肌纤维化的机制以及临床前药理学研究均需进一步探索,因此开发新型药物用于治疗猫HCM以及心肌纤维化的工作任重而道远。
6 小结目前兽医临床上治疗猫HCM的手段有限,猫HCM的特征性病理变化-心肌纤维化对疾病的转归起着重要的作用。研究心肌纤维化在猫HCM发展过程中的作用机制,有助于为治疗疾病提供新思路。鉴于RAAS以及TGF-β1信号通路在心肌纤维化发展中的重要性,探索有效的靶向抑制RAAS以及TGF-β1信号通路将是猫心肌纤维化药物未来开发的重点方向。
[1] |
MACDONALD K A, KITTLESON M D, LARSON R F, et al. The effect of ramipril on left ventricular mass, myocardial fibrosis, diastolic function, and plasma neurohormones in maine coon cats with familial hypertrophic cardiomyopathy without heart failure[J]. J Vet Intern Med, 2006, 20(5): 1093-1105. DOI:10.1111/j.1939-1676.2006.tb00707.x |
[2] |
FREEMAN L M, RUSH J E, STERN J A, et al. Feline hypertrophic cardiomyopathy: a spontaneous large animal model of human HCM[J]. Cardiol Res, 2017, 8(4): 139-142. DOI:10.14740/cr578w |
[3] |
WILKIE L J, SMITH K, FUENTES V L. Cardiac pathology findings in 252 cats presented for necropsy; a comparison of cats with unexpected death versus other deaths[J]. J Vet Cardiol, 2015, 17(Suppl 1): S329-S340. |
[4] |
NGUYEN T P, QU Z L, WEISS J N. Cardiac fibrosis and arrhythmogenesis: The road to repair is paved with perils[J]. J Mol Cell Cardiol, 2014, 70: 83-91. DOI:10.1016/j.yjmcc.2013.10.018 |
[5] |
FOX P R, KEENE B W, LAMB K, et al. International collaborative study to assess cardiovascular risk and evaluate long-term health in cats with preclinical hypertrophic cardiomyopathy and apparently healthy cats: the REVEAL study[J]. J Vet Intern Med, 2018, 32(3): 930-943. DOI:10.1111/jvim.15122 |
[6] |
PAYNE J R, BRODBELT D C, FUENTES V L. Cardiomyopathy prevalence in 780 apparently healthy cats in rehoming centres (the CatScan study)[J]. J Vet Cardiol, 2015, 17(Suppl 1): S244-S257. |
[7] |
TREHIOU-SECHI E, TISSIER R, GOUNI V, et al. Comparative echocardiographic and clinical features of hypertrophic cardiomyopathy in 5 breeds of cats: a retrospective analysis of 344 cases (2001-2011)[J]. J Vet Intern Med, 2012, 26(3): 532-541. DOI:10.1111/j.1939-1676.2012.00906.x |
[8] |
MEURS K M, NORGARD M M, EDERER M M, et al. A substitution mutation in the myosin binding protein C gene in ragdoll hypertrophic cardiomyopathy[J]. Genomics, 2007, 90(2): 261-264. DOI:10.1016/j.ygeno.2007.04.007 |
[9] |
BORGEAT K, CASAMIAN-SORROSAL D, Helps C, et al. Association of the myosin binding protein C3 mutation (MYBPC3 R820 W) with cardiac death in a survey of 236 Ragdoll cats[J]. J Vet Cardiol, 2014, 16(2): 73-80. DOI:10.1016/j.jvc.2014.03.005 |
[10] |
GRANSTRÖM S, GODIKSEN M T N, CHRISTIANSEN M, et al. Prevalence of hypertrophic cardiomyopathy in a cohort of British shorthair cats in Denmark[J]. J Vet Intern Med, 2011, 25(4): 866-871. DOI:10.1111/j.1939-1676.2011.0751.x |
[11] |
CHETBOUL V, PETIT A, GOUNI V, et al. Prospective echocardiographic and tissue Doppler screening of a large Sphynx cat population: Reference ranges, heart disease prevalence and genetic aspects[J]. J Vet Cardiol, 2012, 14(4): 497-509. DOI:10.1016/j.jvc.2012.08.001 |
[12] |
MÄRZ I, WILKIE L J, HARRINGTON N, et al. Familial cardiomyopathy in Norwegian Forest cats[J]. J Feline Med Surg, 2015, 17(8): 681-691. DOI:10.1177/1098612X14553686 |
[13] |
MEURS K M, SANCHEZ X, DAVID R M, et al. A cardiac myosin binding protein C mutation in the Maine Coon cat with familial hypertrophic cardiomyopathy[J]. Hum Mol Genet, 2005, 14(23): 3587-3593. DOI:10.1093/hmg/ddi386 |
[14] |
NOVO MATOS J, PEREIRA N, GLAUS T, et al. Transient myocardial thickening in cats associated with heart failure[J]. J Vet Intern Med, 2018, 32(1): 48-56. DOI:10.1111/jvim.14897 |
[15] |
LUIS FUENTES V, ABBOTT J, CHETBOUL V, et al. ACVIM consensus statement guidelines for the classification, diagnosis, and management of cardiomyopathies in cats[J]. J Vet Intern Med, 2020, 34(3): 1062-1077. DOI:10.1111/jvim.15745 |
[16] |
ELLIOTT P, MCKENNA W J. Hypertrophic cardiomyopathy[J]. Lancet, 2004, 363(9424): 1881-1891. DOI:10.1016/S0140-6736(04)16358-7 |
[17] |
AMBERGER C N, GLARDON O, GLAUS T, et al. Effects of benazepril in the treatment of feline hypertrophic cardiomyopathy Results of a prospective, open-label, multicenter clinical trial[J]. J Vet Cardiol, 1999, 1(1): 19-26. DOI:10.1016/S1760-2734(06)70026-1 |
[18] |
KING J N, MARTIN M, CHETBOUL V, et al. Evaluation of benazepril in cats with heart disease in a prospective, randomized, blinded, placebo-controlled clinical trial[J]. J Vet Intern Med, 2019, 33(6): 2559-2571. DOI:10.1111/jvim.15572 |
[19] |
HOGAN D F. Feline cardiogenic arterial thromboembolism: prevention and therapy[J]. Vet Clin North Am Small Anim Pract, 2017, 47(5): 1065-1082. DOI:10.1016/j.cvsm.2017.05.001 |
[20] |
HOGAN D F, FOX P R, JACOB K, et al. Secondary prevention of cardiogenic arterial thromboembolism in the cat: the double-blind, randomized, positive-controlled feline arterial thromboembolism; clopidogrel vs. aspirin trial (FAT CAT)[J]. J Vet Cardiol, 2015, 17: S306-S317. DOI:10.1016/j.jvc.2015.10.004 |
[21] |
GREEN E M, WAKIMOTO H, ANDERSON R L, et al. A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice[J]. Science, 2016, 351(6273): 617-621. DOI:10.1126/science.aad3456 |
[22] |
STERN J A, MARKOVA S, UEDA Y, et al. A small molecule inhibitor of sarcomere contractility acutely relieves left ventricular outflow tract obstruction in feline hypertrophic cardiomyopathy[J]. PLoS One, 2016, 11(12): e0168407. DOI:10.1371/journal.pone.0168407 |
[23] |
OLIVOTTO I, OREZIAK A, BARRIALES-VILLA R, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial[J]. Lancet, 2020, 396(10253): 759-769. DOI:10.1016/S0140-6736(20)31792-X |
[24] |
FERGUSON B S, STERN J A, OLDACH M S, et al. Acute effects of a mavacamten-like myosin-inhibitor (MYK-581 in a feline model of obstructed hypertrophic cardiomyopathy: evidence of improved ventricular filling (beyond obstruction reprieve)[J]. Eur Heart J, 2020, 41(S2): ehaa946. 3713. |
[25] |
HO C Y, LÓPEZ B, COELHO-FILHO O R, et al. Myocardial fibrosis as an early manifestation of hypertrophic cardiomyopathy[J]. N Engl J Med, 2010, 363(6): 552-563. DOI:10.1056/NEJMoa1002659 |
[26] |
DAVIES M J, MCKENNA W J. Hypertrophic cardiomyopathy—pathology and pathogenesis[J]. Histopathology, 1995, 26(6): 493-500. DOI:10.1111/j.1365-2559.1995.tb00267.x |
[27] |
MEWTON N, LIU C Y, CROISILLE P, et al. Assessment of myocardial fibrosis with cardiovascular magnetic resonance[J]. J Am Coll Cardiol, 2011, 57(8): 891-903. DOI:10.1016/j.jacc.2010.11.013 |
[28] |
KARAMITSOS T D, ARVANITAKI A, KARVOUNIS H, et al. Myocardial tissue characterization and fibrosis by imaging[J]. JACC Cardiovasc Imag, 2020, 13(5): 1221-1234. DOI:10.1016/j.jcmg.2019.06.030 |
[29] |
KHOR K H, CAMPBELL F E, OWEN H, et al. Myocardial collagen deposition and inflammatory cell infiltration in cats with pre-clinical hypertrophic cardiomyopathy[J]. Vet J, 2015, 203(2): 161-168. DOI:10.1016/j.tvjl.2014.11.018 |
[30] |
KITZ S, FONFARA S, HAHN S, et al. Feline hypertrophic cardiomyopathy: the consequence of cardiomyocyte-initiated and macrophage-driven remodeling processes?[J]. Vet Pathol, 2019, 56(4): 565-575. DOI:10.1177/0300985819837717 |
[31] |
NOVO MATOS J, GARCIA-CANADILLA P, SIMCOCK I C, et al. Micro-computed tomography (micro-CT) for the assessment of myocardial disarray, fibrosis and ventricular mass in a feline model of hypertrophic cardiomyopathy[J]. Sci Rep, 2020, 10(1): 20169. DOI:10.1038/s41598-020-76809-5 |
[32] |
CESTA M F, BATY C J, KEENE B W, et al. Pathology of end-stage remodeling in a family of cats with hypertrophic cardiomyopathy[J]. Vet Pathol, 2005, 42(4): 458-467. DOI:10.1354/vp.42-4-458 |
[33] |
BIASATO I, FRANCESCONE L, LA ROSA G, et al. Anatomopathological staging of feline hypertrophic cardiomyopathy through quantitative evaluation based on morphometric and histopathological data[J]. Res Vet Sci, 2015, 102: 136-141. DOI:10.1016/j.rvsc.2015.08.004 |
[34] |
CHRISTIANSEN L B, PRATS C, HYTTEL P, et al. Ultrastructural myocardial changes in seven cats with spontaneous hypertrophic cardiomyopathy[J]. J Vet Cardiol, 2015, 17(Suppl 1): S220-S232. |
[35] |
GALLO E M, LOCH D C, HABASHI J P, et al. Angiotensin Ⅱ-dependent TGF-β signaling contributes to Loeys-Dietz syndrome vascular pathogenesis[J]. J Clin Invest, 2014, 124(1): 448-460. DOI:10.1172/JCI69666 |
[36] |
LANG C C, STRUTHERS A D. Targeting the renin-angiotensin-aldosterone system in heart failure[J]. Nat Rev Cardiol, 2013, 10(3): 125-134. DOI:10.1038/nrcardio.2012.196 |
[37] |
LI Y, CAI X J, GUAN Y Q, et al. Adiponectin upregulates MiR-133a in cardiac hypertrophy through AMPK activation and reduced ERK1/2 phosphorylation[J]. PLoS One, 2016, 11(2): e0148482. DOI:10.1371/journal.pone.0148482 |
[38] |
YANG T, CHEN Y Y, LIU J R, et al. Natural products against renin-angiotensin system for antifibrosis therapy[J]. Eur J Med Chem, 2019, 179: 623-633. DOI:10.1016/j.ejmech.2019.06.091 |
[39] |
AMES M K, ATKINS C E, PITT B. The renin‐angiotensin‐aldosterone system and its suppression[J]. J Vet Intern Med, 2019, 33(2): 363-382. DOI:10.1111/jvim.15454 |
[40] |
SEIFARTH C, TRENKEL S, SCHOBEL H, et al. Influence of antihypertensive medication on aldosterone and renin concentration in the differential diagnosis of essential hypertension and primary aldosteronism[J]. Clin Endocrinol, 2002, 57(4): 457-465. DOI:10.1046/j.1365-2265.2002.01613.x |
[41] |
GRAY M O, LONG C S, KALINYAK J E, et al. Angiotensin Ⅱ stimulates cardiac myocyte hypertrophy via paracrine release of TGF-β1 and endothelin-1 from fibroblasts[J]. Cardiovasc Res, 1998, 40(2): 352-363. DOI:10.1016/S0008-6363(98)00121-7 |
[42] |
CAMPBELL S E, KATWA L C. Angiotensin Ⅱ stimulated expression of transforming growth factor-β1 in cardiac fibroblasts and myofibroblasts[J]. J Mol Cell Cardiol, 1997, 29(7): 1947-1958. DOI:10.1006/jmcc.1997.0435 |
[43] |
RUBTSOV Y P, RUDENSKY A Y. TGFβ signalling in control of T-cell-mediated self-reactivity[J]. Nat Rev Immunol, 2007, 7(6): 443-453. DOI:10.1038/nri2095 |
[44] |
ROLDÁN V, MARÍN F, GIMENO J R, et al. Matrix metalloproteinases and tissue remodeling in hypertrophic cardiomyopathy[J]. Am Heart J, 2008, 156(1): 85-91. DOI:10.1016/j.ahj.2008.01.035 |
[45] |
BUJAK M, FRANGOGIANNIS N G. The role of TGF-β signaling in myocardial infarction and cardiac remodeling[J]. Cardiovasc Res, 2007, 74(2): 184-195. DOI:10.1016/j.cardiores.2006.10.002 |
[46] |
KOITABASHI N, DANNER T, ZAIMAN A L, et al. Pivotal role of cardiomyocyte TGF-β signaling in the murine pathological response to sustained pressure overload[J]. J Clin Invest, 2011, 121(6): 2301-2312. DOI:10.1172/JCI44824 |
[47] |
FUJIO K, KOMAI T, INOUE M, et al. Revisiting the regulatory roles of the TGF-β family of cytokines[J]. Autoimmun Rev, 2016, 15(9): 917-922. DOI:10.1016/j.autrev.2016.07.007 |
[48] |
KHALIL H, KANISICAK O, PRASAD V, et al. Fibroblast-specific TGF-β-Smad2/3 signaling underlies cardiac fibrosis[J]. J Clin Invest, 2017, 127(10): 3770-3783. DOI:10.1172/JCI94753 |
[49] |
YUE Y Y, MENG K, PU Y J, et al. Transforming growth factor beta (TGF-β) mediates cardiac fibrosis and induces diabetic cardiomyopathy[J]. Diabetes Res Clin Pract, 2017, 133: 124-130. DOI:10.1016/j.diabres.2017.08.018 |
[50] |
YUAN M, HAI Z, ZHU X X, et al. Transforming growth factor β: A potential biomarker and therapeutic target of ventricular remodeling[J]. Oncotarget, 2017, 8(32): 53780-53790. DOI:10.18632/oncotarget.17255 |
[51] |
AUPPERLE H, BALDAUF K, MÄRZ I. An immunohistochemical study of feline myocardial fibrosis[J]. J Comparat Pathol, 2011, 145(2-3): 158-173. DOI:10.1016/j.jcpa.2010.12.003 |
[52] |
FONFARA S, HETZEL U, HAHN S, et al. Age-and gender-dependent myocardial transcription patterns of cytokines and extracellular matrix remodelling enzymes in cats with non-cardiac diseases[J]. Exp Gerontol, 2015, 72: 117-123. DOI:10.1016/j.exger.2015.09.018 |
[53] |
COLSTON J T, BOYLSTON W H, FELDMAN M D, et al. Interleukin-18 knockout mice display maladaptive cardiac hypertrophy in response to pressure overload[J]. Biochem Biophys Res Commun, 2007, 354(2): 552-558. DOI:10.1016/j.bbrc.2007.01.030 |
[54] |
YU Q L, VAZQUEZ R, KHOJEINI E V, et al. IL-18 induction of osteopontin mediates cardiac fibrosis and diastolic dysfunction in mice[J]. Am J Physiol Heart Circulat Physiol, 2009, 297(1): H76-H85. DOI:10.1152/ajpheart.01285.2008 |
[55] |
HEDAYAT M, MAHMOUDI M J, ROSE N R, et al. Proinflammatory cytokines in heart failure: double-edged swords[J]. Heart Fail Rev, 2010, 15(6): 543-562. DOI:10.1007/s10741-010-9168-4 |
[56] |
FIX C, BINGHAM K, CARVER W. Effects of interleukin-18 on cardiac fibroblast function and gene expression[J]. Cytokine, 2011, 53(1): 19-28. DOI:10.1016/j.cyto.2010.10.002 |
[57] |
PAYNE J, LUIS FUENTES V, BOSWOOD A, et al. Population characteristics and survival in 127 referred cats with hypertrophic cardiomyopathy (1997 to 2005)[J]. J Small Anim Pract, 2010, 51(10): 540-547. DOI:10.1111/j.1748-5827.2010.00989.x |
[58] |
MANABE I, SHINDO T, NAGAI R. Gene expression in fibroblasts and fibrosis: involvement in cardiac hypertrophy[J]. Circul Res, 2002, 91(12): 1103-1113. DOI:10.1161/01.RES.0000046452.67724.B8 |
[59] |
CUI N, HU M, KHALIL R A. Biochemical and biological attributes of matrix metalloproteinases[J]. Progr Mol Biol Trans Sci, 2017, 147: 1-73. |
[60] |
SEGURA A M, FRAZIER O H, BUJA L M. Fibrosis and heart failure[J]. Heart Fail Rev, 2014, 19(2): 173-185. DOI:10.1007/s10741-012-9365-4 |
[61] |
KOGA M, KURAMOCHI M, KARIM M R, et al. Immunohistochemical characterization of myofibroblasts appearing in isoproterenol-induced rat myocardial fibrosis[J]. J Vet Med Sci, 2019, 81(1): 127-133. DOI:10.1292/jvms.18-0599 |
[62] |
LIU W Y, SUN H H, SUN P F. MicroRNA-378 attenuates myocardial fibrosis by inhibiting MAPK/ERK pathway[J]. Eur Rev Med Pharmacol Sci, 2019, 23(10): 4398-4405. |
[63] |
WEBER K, ROSTERT N, BAUERSACHS S, et al. Serum microRNA profiles in cats with hypertrophic cardiomyopathy[J]. Mol Cell Biochem, 2015, 402(1): 171-180. |
[64] |
MITCHELL P S, PARKIN R K, KROH E M, et al. Circulating microRNAs as stable blood-based markers for cancer detection[J]. Proc Natl Acad Sci USA, 2008, 105(30): 10513-10518. DOI:10.1073/pnas.0804549105 |
[65] |
BOMBACK A S, REKHTMAN Y, KLEMMER P J, et al. Aldosterone breakthrough during aliskiren, valsartan, and combination (aliskiren+valsartan) therapy[J]. J Am Soc Hypertens, 2012, 6(5): 338-345. DOI:10.1016/j.jash.2012.07.003 |
[66] |
CHEN H, LI M, LIU L, et al. Telmisartan improves myocardial remodeling by inhibiting leptin autocrine activity and activating PPARγ[J]. Exp Biol Med, 2020, 245(7): 654-666. DOI:10.1177/1535370220908215 |
[67] |
TSYBOULEVA N, ZHANG L F, CHEN S, et al. Aldosterone, through novel signaling proteins, is a fundamental molecular bridge between the genetic defect and the cardiac phenotype of hypertrophic cardiomyopathy[J]. Circulation, 2004, 109(10): 1284-1291. DOI:10.1161/01.CIR.0000121426.43044.2B |
[68] |
MACDONALD K A, KITTLESON M D, KASS P H. Effect of spironolactone on diastolic function and left ventricular mass in Maine Coon cats with familial hypertrophic cardiomyopathy[J]. J Vet Intern Med, 2008, 22(2): 335-341. DOI:10.1111/j.1939-1676.2008.0049.x |
[69] |
LÓPEZ B, QUEREJETA R, GONZÁLEZ A, et al. Impact of treatment on myocardial Lysyl oxidase expression and collagen cross-linking in patients with heart failure[J]. Hypertension, 2009, 53(2): 236-242. DOI:10.1161/HYPERTENSIONAHA.108.125278 |
[70] |
POISSONNIER C, GHAZAL S, PASSAVIN P, et al. Tolerance of torasemide in cats with congestive heart failure: a retrospective study on 21 cases (2016-2019)[J]. BMC Vet Res, 2020, 16(1): 339. DOI:10.1186/s12917-020-02554-6 |
[71] |
曹蕾, 刘乃丰. 他汀类药物干预心肌纤维化的机制[J]. 东南大学学报: 医学版, 2012, 31(4): 496-500. CAO L, LIU N F. Mechanism of statin intervention on myocardial fibrosis[J]. J Southeast Univ: Med Ed, 2012, 31(4): 496-500. (in Chinese) |
[72] |
MARTIN J, DENVER R, BAILEY M, et al. In vitro inhibitory effects of atorvastatin on cardiac fibroblasts: Implications for ventricular remodelling[J]. Clin Exp Pharmacol Physiol, 2005, 32(9): 697-701. DOI:10.1111/j.1440-1681.2005.04256.x |
[73] |
GELLIBERT F, DE GOUVILLE A C, WOOLVEN J, et al. Discovery of 4-{4-[3-(pyridin-2-yl)-1H-pyrazol-4-yl]pyridin-2-yl}-N-(tetrahydro-2H-pyran-4-yl)benzamide (GW788388): a potent, selective, and orally active transforming growth factor-β type Ⅰ receptor inhibitor[J]. J Med Chem, 2006, 49(7): 2210-2221. DOI:10.1021/jm0509905 |
[74] |
LIU C H, LIM S T, TEO M H Y, et al. Collaborative regulation of LRG1 by TGF-β1 and PPAR-β/δ modulates chronic pressure overload-induced cardiac fibrosis[J]. Circul Heart Fail, 2019, 12(12): e005962. DOI:10.1161/CIRCHEARTFAILURE.119.005962 |
[75] |
LIU M M, KÖSTER L S, FOSGATE G T, et al. Cardiovascular‐renal axis disorder and acute‐phase proteins in cats with congestive heart failure caused by primary cardiomyopathy[J]. J Vet Intern Med, 2020, 34(3): 1078-1090. DOI:10.1111/jvim.15757 |
[76] |
YU Y H, ZHANG Y H, DING Y Q, et al. MicroRNA-99b-3p promotes angiotensin Ⅱ-induced cardiac fibrosis in mice by targeting GSK-3β[J]. Acta Pharmacol Sin, 2021, 42(5): 715-725. DOI:10.1038/s41401-020-0498-z |
[77] |
JIANG W Y, XIONG Y Y, LI X S, et al. Cardiac fibrosis: cellular effectors, molecular pathways, and exosomal roles[J]. Front Cardiovasc Med, 2021, 8: 715258. DOI:10.3389/fcvm.2021.715258 |
[78] |
陆莹, 彭金咏. 抗心肌纤维化天然产物的研究进展[J]. 中国现代应用药学, 2021, 38(6): 762-768. LU Y, PENG J Y. Advance on natural products against myocardial fibrosis[J]. Chinese Journal of Modern Applied Pharmacy, 2021, 38(6): 762-768. DOI:10.13748/j.cnki.issn1007-7693.2021.06.024 (in Chinese) |
(编辑 白永平)