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

Abstract

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.

The Role of microRNAs in Metabolic Syndrome-Related Oxidative Stress

“…There are numerous studies which reported persistently increased ROS levels in HT, along with vast improvement upon antioxidative treatment [121][122][123][124][125][126][127]. HT is connected with vascular remodeling, increased vasoconstriction and arterial stiffness, activation of immune cells, renal dysfunction, and excitation of sympathetic nervous system.…”

The “Hitchhiker’s Guide to the Galaxy” of Endothelial Dysfunction Markers in Human Fertility

“…Effects of seminal ROS may be neutralized by the homeostatic antioxidant systems, to which belong manganese superoxide dismutase (SOD2), catalase (CAT), glutathione peroxidase 1 (GXP1), and glutathione S transferase (GST) [ 135 ]. This complex enzymatic kit was found also in endothelial cells [ 136 ]. In particular, SOD2 catalyzes the detoxification of superoxide radicals in H2O and O2 in mitochondria [ 136 , 137 ].…”

“…This complex enzymatic kit was found also in endothelial cells [ 136 ]. In particular, SOD2 catalyzes the detoxification of superoxide radicals in H2O and O2 in mitochondria [ 136 , 137 ]. Although the gene sequences encoding these enzymes are phylogenetically conserved, SNPs could modulate their expression levels [ 136 ] and, consequently, interfere with the ROS/antioxidants balance, influencing male fertility [ 136 , 137 ].…”

Beyond Fish Oil Supplementation: The Effects of Alternative Plant Sources of Omega-3 Polyunsaturated Fatty Acids upon Lipid Indexes and Cardiometabolic Biomarkers—An Overview

“…ALA administration to primary cultured endothelial cells induced inhibitions of NAD-dependent deacetylase sirtuin-3 (SIRT3) reduction, superoxide dismutase 2 (SOD2) hyperacetylation, and mitochondrial reactive oxygen species (ROS) overproduction, alongside restoration of autophagic flux under damage induced by treatment with angiotensin II plus TNFα [ 42 , 43 ]. Such effects, apparently attributed to ALA, are in line with mitigation of endothelial dysfunction and experimental hypertension [ 42 ].…”

“…Moreover, substrates for TG synthesis are also decreased by reduced transport of non-esterified fatty acids to hepatocytes, consequently reducing VLDL-C synthesis [ 44 , 48 ]. Nonetheless, as the majority of the cardiometabolic pathways so far elucidated are based on experimental data [ 40 , 41 , 42 , 43 ], a more thorough, critical and applied appraisal of the effects of ALA is needed before any general conclusions can be made.…”