Atherosclerosis and Metabolic Disease

Atherosclerosis and metabolic disease – damage of caloric excess

Obesity and type 2 diabetes are rapidly growing worldwide. These conditions are associated with adipose tissue inflammation, accelerated aging, thrombosis, and atherosclerosis. Our atherosclerosis research group (Figure 1) pursues a translational strategy to test central pathways in mice and validate them in patients. We apply genetic modulation and pharmacological interventions in mice using atherosclerosis and thrombosis models and perform complementary analyses in patients with ACS. These strategies should help us to design novel therapies for both atherosclerosis and metabolic diseases.

Team-Matter.jpg
Figure 1 Atherosclerosis Research Group: Melroy Miranda, PhD; Daniel Gaul, MSc; Tasneem Arsiwala, MSc; Julien Weber, technician; Berry van Tits, PhD (coordination, not on picture); Stephan Winnik, MD, PhD; Christian M. Matter, MD

Caloric restriction and atherothrombosis – protective roles of sirtuins

Caloric restriction is known for decades to confer protection in many species. Yet, the corresponding pathways have only been identified recently. Caloric restriction, by modulating the NAD+/NADH ratio, activates sirtuins which exert numerous beneficial effects on pathways involved in lipid metabolism, inflammation and oxidative stress. Less is known about their role in atherothrombosis.

We have used a combined genetic and pharmacological approach to address the role of Sirt1 in atherothrombosis. Using partial SIRT1 deletion in mice and a pharmacological Sirt1 inhibitor, we have shown atheroprotective and anti-thrombotic effects of SIRT1 that were mediated by NF-kB signaling, the scavenger receptor Lox1 and tissue factor. Moreover, we found that pharmacological SIRT1 activation decreased plasma LDL-cholesterol and atherosclerosis in mice (Miranda et al, Eur Heart J 2015). It reduced hepatic PCSK9 secretion, thus increasing LDL-R expression.

SIRT1 activators are in the pipeline, but their clinical approval is pending. To build a bridge from bench to bedside, we are performing expression analyses in patients with acute coronary syndromes (SPUM-ACS). We are also investigating the role of other sirtuins, such as SIRT3 in atherosclerosis and endothelial dysfunction. Using a loss-of-function approach we found that SIRT3 confers decreased weight gain, but does not affect atherosclerosis (Winnik et al, Basic Res Cardiol 2014).

Obesity and endothelial dysfunction – role of the endothelial mineralocorticoid receptor

Fig-3.jpgWithin a cooperative project at the Zurich Center for Integrative Human Physiology (ZIHP), we showed that endothelial mineralocorticoid receptor (MR) increased endothelial dysfunction in obesity (Schäfer et al, Eur Heart J 2014). These data highlight the potential of MR antagonists to treat early vascular disease in patients with obesity (Figure 2).





Figure 2 Mechanisms of aldosterone-induced endothelial dysfunction in obesity. The expression of NADPH oxidase subunit p22phox can be blocked by both eplerenone and endothelial MR ablation. Therefore, p22phox appears a crucial mediator of aldosterone-induced endothelial dysfunction in aortic endothelial cells of obese mice through genomic or non-genomic effects (Schäfer et al, Eur Heart J 2014).

Publications
  • Stein S. et al. SIRT1, PCSK9 and atherothrombosis, Eur Heart J 2010, Aging 2010, Miranda et al, Eur Heart J 2014
  • Biason-Lauber et al. SIRT1 mutation in patients with type 1 diabetes, Cell Metab 2013
  • Winnik S. et al. SIRT3 and atherosclerosis, Basic Res Card 2014.
  • Schäfer N. et al. Endothelial mineralocorticoid receptor (MR) and endothelial dysfunction, Eur Heart J 2014
Letzte Aktualisierung: 08.09.2016 | Verantwortlich:
Prof. Dr. med. Christian Matter