Abstract
BackgroundInhibitors 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).Methods and ResultsBy 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.ConclusionsThis 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.
Highlights
Systolic heart failure is characterized by a detrimental activation of the sympathetic nervous system (SNS) and the renin-angiotensin system (RAS) [1,2,3], whose pharmacologic blockade has proven to be prognostically beneficial, respectively [4,5,6,7]
By progressive right ventricular pacing, distinct heart failure (HF) stages were induced in 15 rabbits, and 6 animals served as controls (CTRL)
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
Summary
Systolic heart failure is characterized by a detrimental activation of the sympathetic nervous system (SNS) and the renin-angiotensin system (RAS) [1,2,3], whose pharmacologic blockade has proven to be prognostically beneficial, respectively [4,5,6,7]. LCZ696, has recently shown beneficial effects with better tolerance and convincingly confirmed the new pathophysiological concept behind this combined RAS-/NEP-inhibition [14]. By further evaluating this principle, our group was able to demonstrate a positive impact of omapatrilat on structural cardiac remodeling and neurohumoral activation [15], which both could provide a pathophysiologic fundament for the beneficial clinical effects. Inhibitors of the renin angiotensin system and neprilysin (RAS-/NEP-inhibitors) proved to be extraordinarily beneficial in systolic heart failure. We aimed to assess whether RAS-/NEP-inhibition can attenuate mitochondrial adaptations in experimental heart failure (HF)
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