Low-sodium diet induces atherogenesis regardless of lowering blood pressure in hypertensive hyperlipidemic mice

Abstract

This study investigated the influence of sodium restriction and antihypertensive drugs on atherogenesis utilizing hypertensive (H) low-density lipoprotein-receptor knockout mice treated or not with losartan (Los) or hydralazine (Hyd) and fed low-sodium (LS) or normal-sodium (NS) chow. Despite reducing the blood pressure (BP) of H-LS mice, the LS diet caused arterial lipid infiltration due to increased plasma total cholesterol (TC) and triglycerides (TG). Los and Hyd reduced the BP of H-LS mice, and Los effectively prevented arterial injury, likely by reducing plasma TG and nonesterified fatty acids. Aortic lipid infiltration was lower in Los-treated H-LS mice (H-LS+Los) than in normotensive (N)-LS and H-LS mice. Aortic angiotensin II type 1 (AT1) receptor content was greater in H-NS than H-LS mice and in H-LS+Hyd than H-LS+Los mice. Carboxymethyl-lysine (CML) and receptor for advanced glycation end products (RAGE) immunostaining was greater in H-LS than H-NS mice. CML and RAGE levels were lower in LS animals treated with antihypertensive drugs, and Hyd enhanced the AT1 receptor level. Hyd also increased the gene expression of F4/80 but not tumor necrosis factor-α, interleukin (IL)-1β, IL-6, IL-10, intercellular adhesion molecule-1 or cluster of differentiation 66. The novelty of the current study is that in a murine model of simultaneous hypertension and hyperlipidemia, the pleiotropic effect of chronic, severe sodium restriction elicited aortic damage even with reduced BP. These negative effects on the arterial wall were reduced by AT1 receptor antagonism, demonstrating the influence of angiotensin II in atherogenesis induced by a severely LS diet.

Dietary sodium restriction alters muscle lipidomics that relates to insulin resistance in mice

“…Despite reducing BP, severe dietary sodium restriction is related to the development of IR that alters lipoprotein metabolism favoring lipid infiltration in the arterial wall compartment in mice ( 7 , 9 ). Skeletal muscle is the major site of glucose disposal contributing to IR that can be affected by lipid species.…”

“…In addition, FFA derivatives are related to IR in muscle, by imparing the phosphorylation of tyrosine redisues in IRS-1, disrupting insulin signaling ( 33 , 34 ). In dyslipidemic mice on LS, plasma FFAs were also related to the enhanced infiltration of lipids in the aortic arch ( 9 , 10 ).…”

“…In the same animal model, LS impaired the lipoprotein lipase (LPL) activity inducing plasma triacylglycerol (TG) elevation despite normal hepatic TG synthesis ( 8 ). In LDL receptor knockout mice (LDLR KO), LS increased lipid infiltration in the aortic arch as compared with normal-sodium (NS) diet, which was related to the enhanced plasma TG, free fatty acids (FFAs), and cholesterol ( 9 , 10 ). These results indicated a role of severe LS restriction in the induction of IR that ultimately relates to CVD.…”

Restrição intensa de sódio alimentar altera espécies de glicerofosfolipídeos e ácidos graxos no gastrocnêmio, favorece resistência insulínica e elevação de triacilgliceróis

“…Observou-se nestes indivíduos maior produção de aldosterona e ANG II, pela ativação do SRAA, o que se associou à RI avaliada por HOMA-IR (Garg et al, 2010b). Em ratos Sprague-Dawley e Wistar, a redução de sódio alimentar proporcionou, igualmente, a ativação do SRAA, nos quais foram observados aumento de atividade de renina, ANG II e aldosterona plasmáticas (Shao et al, 2013;Nagata et al, 2010 (Fusco et al, 2017;Catanozi et al, 2003). O aumento de AGL circulantes se correlaciona com aumento de AGL de cadeia longa no músculo de camundongos (Zabielski et al, 2014).…”

“…A elevação das concentrações plasmáticas de colesterol, principalmente, nas LDL e a redução da concentração de HDLc são os componentes da dislipidemia, diretamente associados à gênese da lesão aterosclerótica (Tanabe et al, 2010e Wilson et al, 1988. (Fusco et al, 2017).…”