Pharmacological restoration of autophagy reduces hypertension-related stroke occurrence

• Published in: Autophagy 2020-08, Vol.16 (8), p.1468-1481
• Main Authors: Forte, Maurizio, Bianchi, Franca, Cotugno, Maria, Marchitti, Simona, De Falco, Elena, Raffa, Salvatore, Stanzione, Rosita, Di Nonno, Flavio, Chimenti, Isotta, Palmerio, Silvia, Pagano, Francesca, Petrozza, Vincenzo, Micaloni, Andrea, Madonna, Michele, Relucenti, Michela, Torrisi, Maria Rosaria, Frati, Giacomo, Volpe, Massimo, Rubattu, Speranza, Sciarretta, Sebastiano
• Format: Article
• Language: English
• Subjects: Animal model; autophagy; human EPCs; mitochondria; NDUFC2; Research Paper; stroke
• ISSN: 1554-8627; 1554-8635
• DOI: 10.1080/15548627.2019.1687215

The identification of the mechanisms predisposing to stroke may improve its preventive and therapeutic strategies in patients with essential hypertension. The role of macroautophagy/autophagy in the development of hypertension-related stroke needs to be clarified. We hypothesized that a defective autophagy may favor hypertension-related spontaneous stroke by promoting mitochondrial dysfunction. We studied autophagy in the stroke-prone spontaneously hypertensive (SHRSP) rat, which represents a clinically relevant model of stroke associated with high blood pressure. We assessed autophagy, mitophagy and NAD + :NADH levels in brains of SHRSP and stroke-resistant SHR fed with high salt diet. Vascular smooth muscle cells silenced for the mitochondrial complex I subunit Ndufc2 gene (NADH:ubiquinone oxidoreductase subunit C2) and cerebral endothelial cells isolated from SHRSP were also used to assess autophagy/mitophagy and mitochondrial function in response to high salt levels. We found a reduction of autophagy in brains of high salt-fed SHRSP. Autophagy impairment was associated with NDUFC2 downregulation, mitochondrial dysfunction and NAD + depletion. Restoration of NAD + levels by nicotinamide administration reactivated autophagy and reduced stroke development in SHRSP. A selective reactivation of autophagy/mitophagy by Tat-Beclin 1 also reduced stroke occurrence, restored autophagy/mitophagy and improved mitochondrial function. Endothelial progenitor cells (EPCs) from subjects homozygous for the thymine allele variant at NDUFC2/rs11237379, which is associated with NDUFC2 deficiency and increased stroke risk, displayed an impairment of autophagy and increased senescence in response to high salt levels. EPC senescence was rescued by Tat-Beclin 1. Pharmacological activation of autophagy may represent a novel therapeutic strategy to reduce stroke occurrence in hypertension. 10 VSMCs: aortic vascular smooth muscle cells; COX4I1/COX IV: cytochrome c oxidase subunit 4I1; ECs: endothelial cells; EPCs: endothelial progenitor cells; JD: Japanese-style diet; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; NAD: nicotinamide adenine dinucleotide; NDUFC2: NADH:ubiquinone oxidoreductase subunit C2; NMN: nicotinamide mononucleotide; RD: regular diet; SHRSP: stroke-prone spontaneously hypertensive rat; SHRSR: stroke-resistant spontaneously hypertensive rat.