A. Crossroads of atherosclerosis and metabolic disease
Obesity is a rapidly growing epidemic worldwide and associated with adipose tissue inflammation, accelerated aging, type 2 diabetes mellitus, thrombosis, and atherosclerosis. Using genetic modulation of key pathways in mice, we aim to improve insight into the common diseases mechanisms. Our atherosclerosis research group (Figure 1) focuses on translational aspects using pharmacological interventions in mice and humans combined with molecular analyses in patients. These strategies should help us to design novel therapies for both, atherosclerosis and metabolic diseases.
B. Sirtuins provide protection in atherothrombosis
Atherosclerosis is a chronic inflammatory disease triggered by an interaction between low-density lipoprotein (LDL) particles and immune cells. Sirtuins are a family of enzymes that are induced by caloric restriction and exert beneficial effects on inflammatory and metabolic pathways. Using genetic SIRT1 deletion in mice, we have shown atheroprotective and anti-thrombotic effects of SIRT1 that were mediated by NF-κB signaling (Figure 2)
Hepatic LDL-receptor (LDL-R) lowers plasma LDL-cholesterol by clearing it from the blood stream. Circulating plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to hepatic LDL-R and targets it for degradation. Thus, lowering PCSK9 activity using an antibody-based strategy emerged as a promising therapy to increase LDL-R and thereby lower plasma LDL-cholesterol. We found that pharmacological SIRT1 activation also decreased plasma LDL-cholesterol and atherosclerosis in mice. It did so by reducing hepatic PCSK9 secretion, thus increasing LDL-R expression. Next to antibody-based lowering of PCSK9 activity pharmacological reduction of hepatic PCSK9 secretion may become an alternative opportunity to lower plasma LDL-cholesterol. (Figure 2).
Since compounds that directly activate SIRT1 are not yet clinically approved, to build a bridge from bench to bedside, we are performing expression analyses in patients with acute coronary syndromes (SPUM-ACS). Furthermore, as part of a cooperation lead by Marc Donath (Basel), we have identified a SIRT1 mutation in a family with type 1 diabetes and inflammatory bowel disease. This phenotype mimicked SIRT1 loss-of-function in mice. Thus, in addition to protection from atherothrombosis, SIRT1 activation may be a promising approach to be tested in patients for protection from diabetes mellitus. We are also investigating the role of SIRT3 in atherothrombosis. Using a loss-of-function approach we found that endogenous SIRT3 confers decreased weight gain, but no effects on atherosclerosis (Winnik et al, Basic Res Cardiol 2013).
C. Obesity and endothelial dysfunction – role of mineralocorticoid receptor (MR)
As part of a ZIHP cooperation, we showed that endothelial mineralocorticoid receptor (MR) increased endothelial dysfunction in obesity (Schäfer et al, EHJ 2013). These data highlight the potential of mineralocorticoid receptor antagonists to treat incipient vascular disease in patients with obesity (Figure 3).
- SIRT1, PCSK9 and atherothrombosis: S. Stein et al, Eur Heart J 2010, Aging 2010, Miranda et al, Eur Heart J 2014
- SIRT1 mutation in patients with type 1 diabetes: Biason-Lauber et al, Cell Metab 2013 - SIRT3 and atherosclerosis: S. Winnik et al, Basic Res Card 2014.
- Endothelial mineralocorticoid receptor (MR) and endothelial dysfunction: N. Schäfer et al, Eur Heart J 2014