Mg supplementation attenuates ritonavir-induced hyperlipidemia, oxidative stress, and cardiac dysfunction in rats

Am J Physiol Regul Integr Comp Physiol. 2013 Nov 15;305(10):R1102-11. doi: 10.1152/ajpregu.00268.2013. Epub 2013 Sep 18.


Use of protease inhibitors (PI) in HIV patients is associated with hyperlipidemia and increased risk of coronary heart disease. Chronic systemic and cardiac effects of ritonavir (RTV), a universal PI booster, and Mg supplementation were examined. RTV was administered (75 mg·kg(-1)·day(-1) po) to Lewis × Brown-Norway hybrid (LBNF1) rats for up to 8 wk; significant increases in plasma triglyceride and cholesterol occurred from 8 days to 8 wk. At 5 wk, the expression of selected hepatic genes (CYP7A1, CITED2, G6PC, and ME-1), which are key to lipid catabolism/synthesis, were altered toward lipogenesis. Dietary Mg supplementation (six-fold higher) completely reversed the altered expression of these genes and attenuated both hypertriglyceridemia and hypercholesterolemia. Neutrophils isolated from the RTV-treated rats displayed a three-fold higher basal and a twofold higher stimulated superoxide production; plasma isoprostane and red blood cell (RBC) GSSG levels were elevated two- to three-fold. All oxidative indices were normalized by Mg supplementation. After 5 wk, RTV caused significant decreases in cardiac left ventricular (LV) shortening fraction and LV ejection fraction; mitral valve early/late atrial ventricular filling (E/A) ratio was reduced accompanied by LV posterior wall thinning. Immunohistochemical staining revealed significant white blood cell (WBC) infiltration (5 wk) and prominent fibrosis (8 wk) in the RTV hearts. Mg supplementation attenuated RTV-induced declines in systolic and diastolic (improved mitral valve E/A ratio) function (>70%), lessened LV posterior wall thinning (by 75%), and substantially decreased the pathological markers. The known clinical hyperlipidemia effects of RTV can be mimicked in the LBNF1 rats; in association, systemic oxidative stress and progressive cardiac dysfunction occurred. Remarkably, Mg supplementation alone suppressed RTV-mediated hyperlipidemia, oxidative stress, and cardiac dysfunction.

Keywords: HIV-1 protease inhibitor ritonavir; cardiac dysfunction; dietary Mg supplementation; hepatic metabolic gene regulation; hyperlipidemia; oxidative stress.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animal Feed
  • Animals
  • Diet
  • Dietary Supplements
  • Gene Expression Regulation / drug effects
  • HIV Protease Inhibitors / toxicity
  • Heart Diseases / chemically induced*
  • Heart Diseases / drug therapy
  • Hyperlipidemias / chemically induced*
  • Magnesium / therapeutic use*
  • Male
  • Oxidative Stress / drug effects*
  • Rats
  • Ritonavir / toxicity*
  • Weight Gain


  • HIV Protease Inhibitors
  • Magnesium
  • Ritonavir