The Mitochondrial‐targeted Antioxidant MitoQ Attenuates LV Dysfunction and Gene Expression Related to Oxidative Stress in Cardiomyocyte‐specific GPER KO Female Mice

Abstract

IntroductionLow‐grade systemic inflammation associates with both postmenopause and the development of heart failure (HF). Given that markers of inflammation and oxidative stress predict incident HF, inflammation may have a direct effect on the estrogen‐deficient myocardium, possibly through increased oxidative stress. In ovariectomized (OVX) models of aging and hypertension, we've shown that estradiol (E2) or activation of the G‐protein coupled estrogen receptor, GPER, by its specific agonist G1, improves diastolic function and limits left ventricular (LV) remodeling. Also, diastolic function decreased and relative wall thickness increased in female mice with cardiomyocyte (CM) specific GPER deletion (GPER KO), with corresponding CM transcriptome alterations in mitochondrial and inflammatory response genes when compared to age‐matched wild type (WT) littermates. To corroborate a potential antioxidant defense role for GPER in the female heart, we determined the efficacy of a mitochondrial‐specific antioxidant, mitoquinone (MitoQ), on ameliorating cardiac dysfunction and the expression of oxidative stress‐related genes in LVs from GPER KO mice.Methods15 GPER KO and 14 WT littermates (6 mo) were randomized to receive either 8 weeks of oral treatment with MitoQ (KO‐MQ: n=8; WT‐MQ: n=7) or its vehicle (KO‐V: n=7; WT‐V: n=7). Tail cuff blood pressure and echocardiograms were obtained prior to sacrifice. LV samples (3 mice/group) were processed using the RT‐qPCR/Reverse transcriptase‐quantitative Polymerase Chain Reaction method for expression of 84 genes related to oxidative stress and oxidative defense. Genes that were 3‐times higher (hyper‐expression), or 3‐times lower (hypo‐expression), than genes from WT‐V were used for comparison. Data were analyzed by ANOVA (significance P<0.05).ResultsGPER knockdown resulted in reductions in fractional shortening (%FS) and myocardial relaxation (e′) and increases in filling pressure (E/e′), without altering blood pressure. MitoQ lessened the dysfunctional cardiac phenotype in KO, but did not modify the normal functioning WT heart (Fig 1). MitoQ‐mediated improvements in cardiac function occurred together with a blunting of oxidative stress genes. Twenty‐one genes relating to oxidative stress were hyper‐expressed in KO‐V hearts while only 5 genes met the criteria for over‐expression in KO‐MQ hearts (Fig 2). Of the 5 concurrently expressed genes, MitoQ blunted over‐expression by 24 to 48% when compared to vehicle. Only hearts from KO‐V exhibited hyper‐expression of Epx (Eosinophil peroxidase), Hspa1a (Heat shock 70), Rag2 (Recombination activating gene 2), Txn1 (Thioredoxin), Nox1 (NADPH oxidase 1), Gpx3 (Glutathione peroxidase 3), and Apoe (Apolipoprotein) genes. The antioxidant gene for glutathione reductase, Gstk, was under‐expressed in KO‐V but not in KO‐MQ hearts.ConclusionThese data show that mitochondria‐derived oxidative stress has an important role in the dysfunction from GPER KO and that mitochondrial targeted anti‐oxidants may be promising strategies to limit or defend against cardiac oxidative stress to preserve cardiac function/structure after E2 loss/GPER deactivation from surgery or menopause.Support or Funding InformationNIH AG033727 (LG); NIH HL051952 (LG and CMF)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.