Renin–angiotensin system inhibitors protect against age-related changes in rat liver mitochondrial DNA content and gene expression

Cavanagh, Elena M.V. de; Flores, Idhaliz; Ferder, Marcelo; Inserra, Felipe; Ferder, León

doi:10.1016/j.exger.2008.08.007

Cited by 26 publications

(23 citation statements)

References 71 publications

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“…The β‐actin gene amplification acted as an internal control. The details of the primer sequences (Mikula et al ., ; de Cavanagh et al ., ; Ding et al ., ) for the various genes studied are given in Supporting Information Table S1. Amplification specificity was controlled by melting curve analysis.…”

Section: Methodsmentioning

confidence: 99%

Adaptability to hypobaric hypoxia is facilitated through mitochondrial bioenergetics: an in vivo study

Loganathan

Boopathy

2013

British J Pharmacology

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Keywordshigh-altitude pulmonary oedema; dexamethasone; oestrogen-related receptor-a; hypobaric hypoxia; mitofusin-2; mitochondrial fission; mitochondrial biogenesis; oxidative phosphorylation ---------------------------------------------------------------- BACKGROUND AND PURPOSEHigh-altitude pulmonary oedema (HAPE) experienced under high-altitude conditions is attributed to mitochondrial redox distress. Hence, hypobaric hypoxia (HH)-induced alteration in expression of mitochondrial biogenesis and dynamics genes was determined in rat lung. Further, such alteration was correlated with expression of mitochondrial DNA (mtDNA)-encoded oxidative phosphorylation (mtOXPHOS) genes. The prophylactic effect of dexamethasone (DEX) in counteracting the HH-induced mitochondrial distress was used as control to understand adaptation to high-altitude exposure. EXPERIMENTAL APPROACHRats pretreated with DEX were exposed to normobaric normoxia (NN) or HH. HH-induced injury was assessed as an increase in lung water content, tissue damage and oxidant generation. Mitochondrial number, mtDNA content and mtOXPHOS activities were measured to determine mitochondrial function. The expression of mitochondrial biogenesis, dynamics and mtOXPHOS genes was studied. KEY RESULTSHH-induced lung injury was associated with decreased mitochondrial number, mtDNA content and mtOXPHOS activities. HH exposure decreased the nuclear gene oestrogen-related receptor-a (ERRa), which interacts with PPAR-g coactivator-1a (PGC-1a) in controlling mitochondrial metabolism. Consequently, mtOXPHOS transcripts are repressed under HH. Further, HH modulated mitochondrial dynamics by decreasing mitofusin 2 (Mfn2) and augmenting fission 1 (Fis1) and dynamin-related protein 1 (Drp1) expression. Nevertheless, DEX treatment under NN (i.e. adaptation to HH) did not affect mitochondrial biogenesis and dynamics, but increased mtOXPHOS transcripts. Further, mtOXPHOS activities increased together with reduced oxidant generation. Also, DEX pretreatment normalized ERRa along with mitochondrial dynamics genes and increased mtOXPHOS transcripts to elicit the mitochondrial function under HH. CONCLUSIONS AND IMPLICATIONSHH stress (HAPE)-mediated mitochondrial dysfunction is due to repressed ERRa and mtOXPHOS transcripts. Thus, ERRa-mediated protection of mitochondrial bioenergetics might be the likely candidate required for lung adaptation to HH. AbbreviationsCO I/II/III, cytochrome c oxidase I/II/III; CS, citrate synthase; Cyt b, cytochrome b; DEX, dexamethasone; Drp1, dynamin-related protein 1; ERRa, oestrogen-related receptor-a; Fis1, fission 1; HAPE, high-altitude pulmonary oedema; Mfn1/2, mitofusin1/2; mtDNA, mitochondrial DNA; ND1 to 6, 4L, NADH-dehydrogenase-ubiquinone reductase1 to 6, 4L; nDNA, nuclear DNA; NRF1/2, nuclear respiratory factor 1/2; OXPHOS, oxidative phosphorylation; PGC-1a, PPAR-g coactivator-1a; RNS, reactive nitrogen species; ROS, reactive oxygen species; TFAM, mitochondrial transcription factor A

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Section: Methodsmentioning

confidence: 99%

Adaptability to hypobaric hypoxia is facilitated through mitochondrial bioenergetics: an in vivo study

Loganathan

Boopathy

2013

British J Pharmacology

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“…In these animals the maintenance of an adequate mitochondrial function during aging was due to the enhanced transcription levels of the genes nuclear respiratory factor 1 and peroxisome proliferators activator receptor gamma coactivator-1α that are involved in mitochondrial respiration and biogenesis, respectively. These positive effects on mitochondria maintained the integrity of the hepatocyte system, and prevented liver fibrosis and the infiltration of inflammatory cells during aging [18].…”

Section: Protective Effect Of Inhibiting Angiotensin II On Agingmentioning

confidence: 98%

Angiotensin receptors as determinants of life span

Cassis

Conti

Remuzzi

et al. 2009

Pflugers Arch - Eur J Physiol

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Angiotensin II (Ang II), the central product of renin-angiotensin system, has a role in the etiology of hypertension and in pathophysiology of cardiac and renal diseases in humans. Other functions of Ang II include effects on immune response, inflammation, cell growth and proliferation, which are largely mediated by Ang II type 1 receptor (AT(1)). Several experimental studies have demonstrated that Ang II acts through AT(1) as a mediator of normal aging processes by increasing oxidant damage to mitochondria and in consequences by affecting mitochondrial function. Recently, our group has demonstrated that the inhibition of Ang II activity by targeted disruption of the Agtr1a gene encoding Ang II type 1A receptor (AT(1A)) in mice translates into marked prolongation of life span. The absence of AT(1A) protected multiple organs from oxidative damage and the alleviation of aging-like phenotype was associated with increased number of mitochondria and upregulation of the prosurvival gene sirtuin 3. AT(1) receptor antagonists have been proven safe and well-tolerated for chronic use and are used as a key component of the modern therapy for hypertension and cardiac failure, therefore Ang II/AT(1) pathway represents a feasible therapeutic strategy to prolong life span in humans.

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“…The threshold cycle (C T ) represents the PCR cycle at which an increase in reporter fluorescence above a baseline signal can first be detected. The ratio between the Gapdh content in standard samples and test samples was defined as the normalization factor (Chen et al 2007;de Cavanagh et al 2008;Miard et al 2009;Yanaka et al 2011). …”

Section: Mrna Expression Analysismentioning

confidence: 99%

High-fat diet intake accelerates aging, increases expression of Hsd11b1, and promotes lipid accumulation in liver of SAMP10 mouse

et al. 2011

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An understanding of the mechanisms of aging is important for prevention of age-related diseases. In this study, we examined age-dependent changes in lipid metabolism in the senescence-accelerated mouse (SAM)P10 fed a high-fat diet to investigate the effects of high-fat intake and aging. Tissue weights and biological parameters in plasma and liver were measured at 6 and 12 months old in SAMP10 mice fed a high-fat diet. These mice showed marked increases in liver triacylglycerol and plasma insulin levels with intake of a high-fat diet intake and aging. Lipid accumulation in hepatocytes and morphological aberrations and hypertrophy in pancreatic islets were also promoted by a high-fat diet and aging. To investigate the underlying mechanisms, the activities and mRNA levels for enzymes associated with lipid metabolism in liver were measured. The results indicated that the lipid metabolic system was activated by a high-fat diet and aging. Liver mRNA level for hydroxysteroid 11-beta dehydrogenase 1 (Hsd11b1), which exhibit age-dependent increases and promote insulin secretion, was also markedly increased. These results suggest that a high-fat diet accelerated aging in the liver of SAMP10 mice by increasing liver mRNA level for Hsd11b1, increasing insulin secretion, and promoting lipid accumulation in the liver.

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Renin–angiotensin system inhibitors protect against age-related changes in rat liver mitochondrial DNA content and gene expression

Cited by 26 publications

References 71 publications

Adaptability to hypobaric hypoxia is facilitated through mitochondrial bioenergetics: an in vivo study

Adaptability to hypobaric hypoxia is facilitated through mitochondrial bioenergetics: an in vivo study

Angiotensin receptors as determinants of life span

High-fat diet intake accelerates aging, increases expression of Hsd11b1, and promotes lipid accumulation in liver of SAMP10 mouse

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