Pharmacological restoration of autophagy reduces hypertension-related stroke occurrence

Maurizio Forte, Franca Bianchi, Maria Cotugno, Simona Marchitti, Elena De Falco, Salvatore Raffa, Rosita Stanzione, Flavio Di Nonno, Isotta Chimenti, Silvia Palmerio, Francesca Pagano, Vincenzo Petrozza, Andrea Micaloni, Michele Madonna, Michela Relucenti, Maria Rosaria Torrisi, Giacomo Frati, Massimo Volpe, Speranza Rubattu, Sebastiano Sciarretta

Research output: Contribution to journalArticle

Abstract

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.Abbreviations: 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.

Original languageEnglish
Pages (from-to)1-14
Number of pages14
JournalAutophagy
DOIs
Publication statusE-pub ahead of print - Nov 12 2019

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    Forte, M., Bianchi, F., Cotugno, M., Marchitti, S., De Falco, E., Raffa, S., Stanzione, R., Di Nonno, F., Chimenti, I., Palmerio, S., Pagano, F., Petrozza, V., Micaloni, A., Madonna, M., Relucenti, M., Torrisi, M. R., Frati, G., Volpe, M., Rubattu, S., & Sciarretta, S. (2019). Pharmacological restoration of autophagy reduces hypertension-related stroke occurrence. Autophagy, 1-14. https://doi.org/10.1080/15548627.2019.1687215