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.

Pharmacological restoration of autophagy reduces hypertension-related stroke occurrence / 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. - In: AUTOPHAGY. - ISSN 1554-8627. - (2019), pp. 1-14-14. [10.1080/15548627.2019.1687215]

Pharmacological restoration of autophagy reduces hypertension-related stroke occurrence

Cotugno, Maria
Methodology
;
Marchitti, Simona
Methodology
;
De Falco, Elena
Investigation
;
Raffa, Salvatore
Investigation
;
Stanzione, Rosita
Methodology
;
Di Nonno, Flavio
Methodology
;
Chimenti, Isotta
Formal Analysis
;
Palmerio, Silvia
Methodology
;
Pagano, Francesca
Methodology
;
Petrozza, Vincenzo
Formal Analysis
;
Micaloni, Andrea
Methodology
;
Madonna, Michele
Methodology
;
Relucenti, Michela
Methodology
;
Torrisi, Maria Rosaria
Supervision
;
Frati, Giacomo
Writing – Review & Editing
;
Volpe, Massimo
Resources
;
Rubattu, Speranza
Conceptualization
;
Sciarretta, Sebastiano
Conceptualization
2019

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.
2019
animal model; NDUFC2; autophagy; human EPCs; mitochondria; stroke
01 Pubblicazione su rivista::01a Articolo in rivista
Pharmacological restoration of autophagy reduces hypertension-related stroke occurrence / 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. - In: AUTOPHAGY. - ISSN 1554-8627. - (2019), pp. 1-14-14. [10.1080/15548627.2019.1687215]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1331012
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