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EAS2019 Maastricht - Novel insights into metabolic dysfunction in cardiovascular disease

Tuesday 28 May 2019   (0 Comments)
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Monday 27 May Plenary: Novel insights into metabolic dysfunction in cardiovascular disease

Plenary 1 focused on metabolic dysfunction, with ensuing discussion of potential targets in that may offer potential for therapeutic intervention. Opening the session, Professor Klaus Ley (La Jolla Institute for Allergy and Immunology and Adjunct Professor of Bioengineering at the University of California, San Diego, USA) suggested a role for olfactory receptors in mediating atherosclerosis. Olfactory receptors are seven transmembrane G protein coupled receptors that detect volatile ligands (odorants). Originally identified in the olfactory epithelium, they also exist in other tissues, including mouse and human macrophages in vascular tissues. The diversity of olfactory receptors — and the molecules that activate them — suggests that these may trigger several signalling pathways via the involvement of specific cofactors. Professor Ley discussed novel experimental data in which stimulation of the Olfr2 receptor by octanal, a fatty aldehyde in citrus oils, in conjunction with lipopolysaccharide, promoted calcium flux, increased the production of inflammatory mediators such as interleukin-1β, tumour necrosis factor (TNF), and the chemokines CCL2 and CCL4, as well as nitric oxide synthase (iNOS), resulting in acceleration of atherosclerosis in an Apoe knockout model. In contrast, citranal, an olfr2 antagonist reduced atherosclerosis. A similar response was exhibited in human monocyte-derived macrophages, involving the OR6A2 receptor, which is expressed in human carotid plaques. Given that the gut microbiome produces metabolites such as octanal that act on macrophages to promote atherosclerosis, these findings suggest new possibilities for targeting inflammation involving interaction between the microbiome, macrophages and vascular tissues.

Following on, Professor Peter Carmeliet (Katholieke Universiteit Leuven, Belgium,  a past Anitschkow Award recipient (Innsbruck 2016), revisited angiogenesis, specifically focusing on the role of endothelial metabolism and heterogeneity. Endothelial cell metabolism is essential in the production of energy and maintenance of redox homeostasis in vascular migratory tip cells, proliferating stalk cells, and quiescent phalanx cells. Perturbation of this metabolism, however, impacts the vasculature. Professor Carmeliet gave an elegant overview showing how an omics approach can help to further understanding of the role of endothelial metabolism in angiogenesis, identify new endothelial cell phenotypes, and suggest angiogenic targets and therapeutic strategies in different tissues. For example, metabolic studies have shown that decreased glucose oxidation limits proliferation and reduces collagen synthesis, whereas enhanced glutamine flux increases proline and lysine hydroxylation on collagen.1 Congruency analysis, supported by transcriptomic analysis and proteomics, revealed that dysregulated collagen modification may also contribute to diseases involving the extracellular matrix such as cancer and fibrosis.

The focus shifted to mitochondrial dysfunction, specifically in the context of aging in a subsequent presentation by Professor Douglas R. Seals (University of Colorado Boulder, USA). Endothelial dysfunction and increased arterial stiffness are key mechanisms implicated in age-related vascular dysfunction, in which both inflammation and oxidative stress play a key role. These findings have important significance given that, with an increasingly ageing population, cardiovascular disease prevalence and morbidity are expected to increase exponentially. Moreover, vascular dysfunction associated with aging extends beyond the cardiovascular system, to include effects on cognitive function, kidney disease and metabolic disorders.

Mitochondria-derived oxidative stress plays a key role in cardiovascular aging, as evident by promotion of adverse structural changes, large elastic artery stiffening and exacerbation and maintenance of arterial inflammation.2 Preclinical studies showing that mitochondria-targeted antioxidants can help to ameliorate age-related arterial endothelial dysfunction,3 provided support for translational investigation in man. Professor Seals presented data from a pilot study in healthy older individuals (mean age 68 years) showing that supplementation with mitoQ decreased markers of oxidative stress, and abrogated the effects of oxidative stress-mediated suppression of endothelial function, and that these changes were associated with improvement in aortic stiffness.4 These encouraging results prompt further investigation in larger trials.

Anitschkow Award recipient Professor Helen Hobbs concluded Monday’s Plenary with a discussion of recent research linking a variant in PNPLA3 (palatin-like phospholipase domain-containing 3) with risk for fatty liver disease. Previously, findings from the Dallas Heart Study highlighted marked differences in the prevalence of hepatic steatosis, which was two-fold higher in Hispanics than Black Americans. Genetic analyses based on this cohort revealed that a missense mutation in PNPLA3 (PNPLA3-148M) was present in 49% of Hispanics compared with 23% in white and 17% of Black Americans.5 Concomitant adiposity has been shown to amplify clinical manifestation of this variant on liver fat content.6  However, until recently, the mechanism underlying the effect of this variant was unclear. Professor Hobbs explained how new studies helped to delineate this, showing that this 148M variant disrupts ubiquitylation and proteasomal degradation of PNPLA3, resulting in accumulation of PNPLA3-148M and impaired mobilisation of triglycerides from lipid droplets.7 Importantly, understanding this mechanism offers potential for new strategies targeting PNPLA3 expression, with the ultimate aim of preventing progression of fatty liver disease. These findings have important relevance in the context of the ongoing obesity pandemic, with fatty liver disease now the most prevalent cause of chronic liver disease worldwide.


1. Stegen S, Laperre K, Eelen G, et al. HIF-1α metabolically controls collagen synthesis and modification in chondrocytes. Nature 2019;565:511-5.

2. Seals DR, Justice JN, LaRocca TJ. Physiological geroscience: targeting function to increase healthspan and achieve optimal longevity. J Physiol 2016;594:2001-24.

3. Gioscia-Ryan RA, Battson ML, Cuevas LM, et al. Mitochondria-targeted antioxidant therapy with MitoQ ameliorates aortic stiffening in old mice. J Appl Physiol 2018;124:1194-202.

4. Rossman MJ, Santos-Parker JR, Steward CAC et al. Chronic supplementation with a mitochondrial antioxidant (MitoQ) improves vascular function in healthy older adults. Hypertension 2018;71:1056-63.

5. Romeo S, Kozlitina J, Xing C et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008;40:1461-5.

6. Stender S, Kozlitina J, Nordestgaard BG, et al. Adiposity amplifies the genetic risk of fatty liver disease conferred by multiple loci. Nat Genet 2017;49:842-7.

7. BasuRay S, Smagris E, Cohen JC, Hobbs HH. The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation. Hepatology 2017;66:1111-24.

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