Grois Laura, Hupf Julian, Reinders Jörg, Schröder Josef, Dietl Alexander, Schmid Peter M, Jungbauer Carsten, Resch Markus, Maier Lars S, Luchner Andreas, Birner Christoph
Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany.
Institute of Functional Genomics, University Regensburg, Regensburg, Germany.
PLoS One. 2017 Jan 11;12(1):e0169743. doi: 10.1371/journal.pone.0169743. eCollection 2017.
Inhibitors of the renin angiotensin system and neprilysin (RAS-/NEP-inhibitors) proved to be extraordinarily beneficial in systolic heart failure. Furthermore, compelling evidence exists that impaired mitochondrial pathways are causatively involved in progressive left ventricular (LV) dysfunction. Consequently, we aimed to assess whether RAS-/NEP-inhibition can attenuate mitochondrial adaptations in experimental heart failure (HF).
By progressive right ventricular pacing, distinct HF stages were induced in 15 rabbits, and 6 animals served as controls (CTRL). Six animals with manifest HF (CHF) were treated with the RAS-/NEP-inhibitor omapatrilat. Echocardiographic studies and invasive blood pressure measurements were undertaken during HF progression. Mitochondria were isolated from LV tissue, respectively, and further worked up for proteomic analysis using the SWATH technique. Enzymatic activities of citrate synthase and the electron transfer chain (ETC) complexes I, II, and IV were assessed. Ultrastructural analyses were performed by transmission electron microscopy. During progression to overt HF, intricate expression changes were mainly detected for proteins belonging to the tricarboxylic acid cycle, glucose and fat metabolism, and the ETC complexes, even though ETC complex I, II, or IV enzymatic activities were not significantly influenced. Treatment with a RAS-/NEP-inhibitor then reversed some maladaptive metabolic adaptations, positively influenced the decline of citrate synthase activity, and altered the composition of each respiratory chain complex, even though this was again not accompanied by altered ETC complex enzymatic activities. Finally, ultrastructural evidence pointed to a reduction of autophagolytic and degenerative processes with omapatrilat-treatment.
This study describes complex adaptations of the mitochondrial proteome in experimental tachycardia-induced heart failure and shows that a combined RAS-/NEP-inhibition can beneficially influence mitochondrial key pathways.
肾素血管紧张素系统和中性肽链内切酶抑制剂（RAS-/NEP抑制剂）已被证明对收缩性心力衰竭极为有益。此外，有确凿证据表明线粒体途径受损与进行性左心室（LV）功能障碍存在因果关系。因此，我们旨在评估RAS-/NEP抑制是否能减轻实验性心力衰竭（HF）中的线粒体适应性变化。
通过逐步右心室起搏，在15只兔子中诱导出不同的HF阶段，6只动物作为对照（CTRL）。对6只出现明显HF（CHF）的动物用RAS-/NEP抑制剂奥美帕替拉进行治疗。在HF进展过程中进行超声心动图研究和有创血压测量。分别从LV组织中分离出线粒体，并使用SWATH技术进一步进行蛋白质组分析。评估柠檬酸合酶和电子传递链（ETC）复合物I、II和IV的酶活性。通过透射电子显微镜进行超微结构分析。在进展为明显HF的过程中，主要检测到三羧酸循环、葡萄糖和脂肪代谢以及ETC复合物相关蛋白质的复杂表达变化，尽管ETC复合物I、II或IV的酶活性没有受到显著影响。然后用RAS-/NEP抑制剂治疗可逆转一些适应性不良的代谢变化，对柠檬酸合酶活性的下降产生积极影响，并改变每个呼吸链复合物的组成，尽管这同样没有伴随着ETC复合物酶活性的改变。最后，超微结构证据表明奥美帕替拉治疗可减少自噬和退行性过程。
本研究描述了实验性心动过速诱导的心力衰竭中线粒体蛋白质组的复杂适应性变化，并表明联合RAS-/NEP抑制可有益地影响线粒体关键途径。
