113
695.98
6.16
254

Publication History View all

  • [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondria are often regarded as the cellular powerhouses through their ability to generate ATP, the universal fuel for metabolic processes. However, in recent years mitochondria have been recognised as critical regulators of cell death, inflammation, metabolism, and the generation of reactive oxygen species (ROS). Thus, mitochondrial dysfunction directly promotes cell death, inflammation, and oxidative stress and alters metabolism. These are key processes in atherosclerosis and there is now evidence that mitochondrial DNA (mtDNA) damage leads to mitochondrial dysfunction and promotes atherosclerosis directly. In this review we discuss the recent evidence for and mechanisms linking mtDNA defects and atherosclerosis and suggest areas of mitochondrial biology that are potential therapeutic targets.
    Trends in Endocrinology and Metabolism 09/2014; 25(9). DOI:10.1016/j.tem.2014.06.008
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abdominal aortic aneurysm is an inflammatory disease leading to destructive vascular remodeling and ultimately to lethal aortic rupture. Despite its frequent association with atherosclerosis, compelling studies have shown striking differences and potentially opposite roles of T-cell helper responses in aneurysm as compared with atherosclerosis, casting doubt on the relevance and suitability of T-cell-targeted therapies in this context. Here, we show that selective depletion of T regulatory (Treg) cells using a CD25-specific monoclonal antibody significantly enhances the susceptibility of C57Bl/6 mice to angiotensin II-induced abdominal aortic aneurysm and promotes aortic rupture (n=25-44 mice/group). Similar results are observed in angiotensin II-treated Cd80(-/-)/Cd86(-/-) or Cd28(-/-) mice with impaired Treg cell homeostasis (n=18-23 mice/group). Treg cell depletion is associated with increased immune cell activation and a blunted interleukin (IL)-10 anti-inflammatory response, suggesting an immunoinflammatory imbalance. Interestingly, Il-10(-/-) mice (n=20 mice/group) show increased susceptibility to angiotensin II-induced abdominal aortic aneurysm and aortic rupture and are insensitive to Treg cell depletion. Finally, reconstitution of Cd28(-/-) Treg-deficient mice with Treg cells (n=22 mice/group) restores a balance in the immunoinflammatory response, rescues the animals from increased susceptibility to aneurysm, and prevents aortic dissection. These results identify a critical role for Treg cells and IL-10 in the control of aneurysm formation and its progression to rupture and suggest that therapies targeting Treg responses may be most suited to treat aneurysmal disease.
    Arteriosclerosis Thrombosis and Vascular Biology 08/2013; 33(10). DOI:10.1161/ATVBAHA.113.301280
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondrial DNA (mtDNA) damage occurs in both circulating cells and the vessel wall in human atherosclerosis. However it is unclear whether mtDNA damage directly promotes atherogenesis or is a consequence of tissue damage, which cell types are involved, and whether its effects are only mediated through reactive oxygen species (ROS). MtDNA damage occurred early in the vessel wall in Apolipoprotein E null (ApoE(-/-)) mice, before significant atherosclerosis developed. MtDNA defects were also identified in circulating monocytes and liver, and associated with mitochondrial dysfunction. To determine whether mtDNA damage directly promotes atherosclerosis, we studied ApoE(-/-) mice deficient for mitochondrial polymerase-γ proofreading activity (polG(-/-)/ApoE(-/-)). polG(-/-)/ApoE(-/-) mice showed extensive mtDNA damage and defects in oxidative phosphorylation, but no increase in ROS. polG(-/-)/ApoE(-/-) mice showed increased atherosclerosis, associated with impaired proliferation and apoptosis of vascular smooth muscle cells, and hyperlipidemia. Transplantation with polG(-/-)/ApoE(-/-) bone marrow increased features of plaque vulnerability, and polG(-/-)/ApoE(-/-) monocytes showed increased apoptosis and inflammatory cytokine release. To examine mtDNA damage in human atherosclerosis, we assessed mtDNA adducts in plaques, and in leukocytes from patients who had undergone virtual histology intravascular ultrasound characterization of coronary plaques. Human atherosclerotic plaques showed increased mtDNA damage compared with normal vessels; in contrast, leukocyte mtDNA damage was associated with higher-risk plaques but not plaque burden. We show that mtDNA damage in vessel wall and circulating cells is widespread, causative and indicates higher risk in atherosclerosis. Protection against mtDNA damage and improvement of mitochondrial function are potential areas for new therapeutics.
    Circulation 07/2013; 128(7). DOI:10.1161/CIRCULATIONAHA.113.002271
  • [Show abstract] [Hide abstract]
    ABSTRACT: OBJECTIVE: Different vascular beds show differing susceptibility to the development of atherosclerosis, but the molecular mechanisms underlying these differences are incompletely understood. This study aims to identify factors that contribute to the phenotypic heterogeneity of distinct regions of the adult vasculature.Approach and Results-High-throughput mRNA profiling in adult mice reveals higher expression of the homeobox paralogous genes 6 to 10 (Hox6-10) in the athero-resistant thoracic aorta (TA) than in the athero-susceptible aortic arch (AA). Higher Hox gene expression also occurs in rat and porcine TA, and is maintained in primary smooth muscle cells isolated from TA (TA-SMCs) than in cells from AA (AA-SMCs). This region-specific homeobox gene expression pattern is also observed in human embryonic stem cells differentiated into neuroectoderm-SMCs and paraxial mesoderm-SMCs, which give rise to AA-SMCs and TA-SMCs, respectively. We also find that, compared with AA and AA-SMCs, TA and TA-SMCs have lower activity of the proinflammatory and proatherogenic transcription factor NF-κB and lower expression of NF-κB target genes, at least in part attributable to HOXA9-dependent inhibition. Conversely, NF-κB inhibits HOXA9 promoter activity and mRNA expression in SMCs. CONCLUSIONS: Our findings support a model of Hox6-10-specified positional identity in the adult vasculature that is established by embryonic cues independently of environmental factors and is conserved in different mammalian species. Differential Hox expression contributes to maintaining phenotypic differences between SMCs from athero-resistant and athero-susceptible regions, at least in part through feedback regulatory mechanisms involving inflammatory mediators, for example, reciprocal inhibition between HOXA9 and NF-κB.
    Arteriosclerosis Thrombosis and Vascular Biology 02/2013; 33(6). DOI:10.1161/ATVBAHA.112.300539
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Necrosis can induce profound inflammation or be clinically silent. However, the mechanisms underlying such tissue specificity are unknown. Interleukin-1α (IL-1α) is a key danger signal released upon necrosis that exerts effects on both innate and adaptive immunity and is considered to be constitutively active. In contrast, we have shown that necrosis-induced IL-1α activity is tightly controlled in a cell type-specific manner. Most cell types examined expressed a cytosolic IL-1 receptor 2 (IL-1R2) whose binding to pro-IL-1α inhibited its cytokine activity. In cell types exhibiting a silent necrotic phenotype, IL-1R2 remained associated with pro-IL-1α. Cell types possessing inflammatory necrotic phenotypes either lacked IL-1R2 or had activated caspase-1 before necrosis, which degraded and dissociated IL-1R2 from pro-IL-1α. Full IL-1α activity required cleavage by calpain after necrosis, which increased its affinity for IL-1 receptor 1. Thus, we report a cell type-dependent process that fundamentally governs IL-1α activity postnecrosis and the mechanism allowing conditional release of this blockade.
    Immunity 02/2013; 38(2):285-295. DOI:10.1016/j.immuni.2013.01.008
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Vascular smooth muscle cells (VSMCs) in human atherosclerosis manifest extensive DNA damage and activation of the DNA damage response (DDR), a pathway that coordinates cell cycle arrest and DNA repair, or can trigger apoptosis or cell senescence. Sirtuin 1 deacetylase (SIRT1) regulates cell ageing and energy metabolism, and regulates the DDR through multiple targets. However, the direct role of SIRT1 in atherosclerosis and how SIRT1 in VSMCs might regulate atherosclerosis are unknown. METHODS AND RESULTS: SIRT1 expression was reduced in human atherosclerotic plaques and VSMCs both derived from plaques and undergoing replicative senescence. SIRT1 inhibition reduced DNA repair and induced apoptosis, partly through reduced activation of the repair protein Nijmegen Breakage Syndrome-1 (NBS1) but not p53. Fat feeding reduced SIRT1 and induced DNA damage in VSMCs. VSMCs from mice expressing inactive truncated SIRT1 (Δex4) showed increased oxidized LDL-induced DNA damage and senescence. ApoE(-/-) mice expressing SIRT1(Δex4) only in SMCs demonstrated increased DDR activation and apoptosis, increased atherosclerosis, reduced relative fibrous cap thickness and medial degeneration. CONCLUSIONS: SIRT1 is reduced in human atherosclerosis and is a critical regulator of the DDR and survival in VSMCs. VSMC SIRT1 protects against DNA damage, medial degeneration and atherosclerosis.
    Circulation 12/2012; 127(3). DOI:10.1161/CIRCULATIONAHA.112.124404
  • Atherosclerosis 12/2012; 225(2):e6–e7. DOI:10.1016/j.atherosclerosis.2012.10.023
  • Atherosclerosis 12/2012; 225(2):e6. DOI:10.1016/j.atherosclerosis.2012.10.022
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Human and animal studies suggest that suboptimal early nutrition during critical developmental periods impacts long-term health. For example, maternal overnutrition during pregnancy and lactation in mice programs insulin resistance, obesity, and endothelial dysfunction in the offspring. Here we investigated the effects of diet-induced maternal obesity on the offspring cardiac phenotype and explored potential underlying molecular mechanisms. Dams fed the obesogenic diet were heavier (P < 0.01) and fatter (P < 0.0001) than controls throughout pregnancy and lactation. There was no effect of maternal obesity on offspring body weight or body composition up to 8 wk of age. However, maternal obesity resulted in increased offspring cardiac mass (P < 0.05), increased heart-body weight (P < 0.01), heart weight-tibia length (P < 0.05), increased left ventricular free wall thickness and area (P < 0.01 and P < 0.05, respectively), and increased myocyte width (P < 0.001). Consistent with these structural changes, the expression of molecular markers of cardiac hypertrophy were also increased [Nppb(BNP), Myh7-Myh6(βMHC-αMHC) (both P < 0.05) and mir-133a (P < 0.01)]. Offspring were hyperinsulinemic and displayed increased insulin action through AKT (P < 0.01), ERK (P < 0.05), and mammalian target of rapamycin (P < 0.05). p38MAPK phosphorylation was also increased (P < 0.05), suggesting pathological remodeling. Increased Ncf2(p67(phox)) expression (P < 0.05) and impaired manganese superoxide dismutase levels (P < 0.01) suggested oxidative stress, which was consistent with an increase in levels of 4-hydroxy-2-trans-nonenal (a measure of lipid peroxidation). We propose that maternal diet-induced obesity leads to offspring cardiac hypertrophy, which is independent of offspring obesity but is associated with hyperinsulinemia-induced activation of AKT, mammalian target of rapamycin, ERK, and oxidative stress.
    Endocrinology 10/2012; 153(12). DOI:10.1210/en.2012-1508
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: The epigenomes of healthy and diseased human hearts were recently examined by genome-wide DNA methylation profiling. Repetitive elements, heavily methylated in post-natal tissue, have variable methylation profiles in cancer but methylation of repetitive elements in the heart has never been examined. RESULTS: We analyzed repetitive elements from all repeat families in human myocardial samples, and found that satellite repeat elements were significantly hypomethylated in end-stage cardiomyopathic hearts relative to healthy normal controls. Satellite repeat elements are almost always centromeric or juxtacentromeric, and their overexpression correlates with disease aggressiveness in cancer. Similarly, we found that hypomethylation of satellite repeat elements correlated with up to 27-fold upregulation of the corresponding transcripts in end-stage cardiomyopathic hearts. No other repeat family exhibited differential methylation between healthy and cardiomyopathic hearts, with the exception of the Alu element SINE1/7SL, for which a modestly consistent trend of increased methylation was observed. CONCLUSIONS: Satellite repeat element transcripts, a form of non-coding RNA, have putative functions in maintaining genomic stability and chromosomal integrity. Further studies will be needed to establish the functional significance of these non-coding RNAs in the context of heart failure.
    Genome biology 10/2012; 13(10):R90. DOI:10.1186/gb-2012-13-10-r90
Information provided on this web page is aggregated encyclopedic and bibliographical information relating to the named institution. Information provided is not approved by the institution itself. The institution’s logo (and/or other graphical identification, such as a coat of arms) is used only to identify the institution in a nominal way. Under certain jurisdictions it may be property of the institution.