Cell Death Dis., 2020., Feb 3;11(2):83. doi: 10.1038/s41419-020-2277-7.

α-Linolenic acid but not linolenic acid protects against hypertension: critical role of SIRT3 and autophagic flux.

Li G Wang X Yang H et al.


Although dietary α-linolenic acid (ALA) or linolenic acid (LA) intake was reported to be epidemiologically associated with a lower prevalence of hypertension, recent clinical trials have yielded conflicting results. Comparable experimental evidence for the roles of these two different fatty acids is still lacking and the underlying mechanisms need to be further elucidated. Our data showed that ALA but not LA supplementation alleviated systolic blood pressure elevation and improved ACh-induced, endothelium-dependent vasodilation in both spontaneously hypertensive rats (SHRs) and AngII-induced hypertensive mice. In addition, SHRs displayed reduced vascular Sirtuin 3 (SIRT3) expression, subsequent superoxide dismutase 2 (SOD2) hyperacetylation and mitochondrial ROS overproduction, all of which were ameliorated by ALA but not LA supplementation. In primary cultured endothelial cells, ALA treatment directly inhibited SIRT3 reduction, SOD2 hyperacetylation, mitochondrial ROS overproduction and alleviated autophagic flux impairment induced by AngII plus TNFα treatment. However, these beneficial effects of ALA were completely blocked by silencing SIRT3. Restoration of autophagic flux by rapamycin also inhibited mitochondrial ROS overproduction in endothelial cells exposed to AngII plus TNFα. More interestingly, SIRT3 KO mice developed severe hypertension in response to a low dose of AngII infusion, while ALA supplementation lost its anti-hypertensive and endothelium-protective effects on these mice. Our findings suggest that ALA but not LA supplementation improves endothelial dysfunction and diminishes experimental hypertension by rescuing SIRT3 impairment to restore autophagic flux and mitochondrial redox balance in endothelial cells.

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Key Points

Sirtuins regulate numerous aspects of mitochondrial biology, including metabolic homeostasis, redox balance and mitochondrial dynamics. The associations between mitochondrial Sirtuins impairment and cardiovascular disease have been well established by many preclinical studies. In particular, SIRT3 impairment and the resultant SOD2 hyperacetylation have been demonstrated to induce vascular oxidative stress and contribute to the development of hypertension. Although the anti-oxidative property of ALA has been reported previously, whether SIRT3 plays an important role in the benefits of ALA remain unknown. The present study was designed to comparatively investigate the effects of ALA and LA supplementation against hypertension and the underlying molecular mechanisms. ALA but not LA supplementation rescues SIRT3 reduction, improves endothelial dysfunction and reduces blood pressure elevation in hypertensive animals, thus providing the proof of principle for the benefits of dietary ALA intake against hypertension. SIRT3 plays an important role in the anti-hypertensive effects of ALA by alleviating autophagic flux impairment and inhibiting mitochondrial ROS overproduction in endothelial cells.

The in vitro experiments also indicated that ALA exerted direct antioxidant effect and restored autophagic flux in endothelial cells, which might contribute to the improved endothelial dysfunction and decreased blood pressure in hypertensive animals afforded by ALA supplementation. LA supplementation had no effects on blood pressure and endothelial dysfunction in SHRs, which may be partially attributable to the change of prostacyclin from dilator to constrictor in the LA metabolism of SHRs. ALA supplementation rescued SIRT3 reduction and SOD2 hyperacetylation, improved endothelial dysfunction and reduced blood pressure elevation in hypertensive animals. SIRT3 knockout rendered the mice more susceptible to AngII-induced hypertension and abolished the endothelium-beneficial and antihypertensive effects of ALA supplementation, indicating the critical role of SIRT3 in vascular protective effects of ALA.

The data demonstrate that endothelial SIRT3 reduction is concomitant with dysregulation of autophagic flux in endothelial cells of hypertension, and both could be rescued by ALA administration. In conclusion, the data have demonstrated that ALA supplementation ameliorates endothelial dysfunction and hypertension by rescuing SIRT3 impairment and thus alleviating SOD2 hyperacetylation and autophagic impairment to inhibit vascular oxidative stress, suggesting a novel cardioprotective effect of ALA.