Wirts- und mikrobiomseitige Einflussfaktoren auf die Inflammation bei kardiovaskulären Erkrankungen

Abstract

Cardiovascular diseases such as atherosclerosis and hypertension are characterized by a persistent inflammatory state, the severity of which can be influenced by both intrinsic cellular processes and extrinsic microbial factors. The proteasome as the central protein degradation system served as the cellular target structure in the present study, whose function in the context of atherosclerosis was influenced by the application of a proteasome inhibitor. Taking into account the central role of the proteasome and in order to avoid toxic effects, low concentrations of the proteasome inhibitor bortezomib were used to influence experimental atherosclerosis in LDLR -/- mice. An early stage of atherosclerosis could be favorably influenced by low-dose proteasome inhibition. Mechanistically, anti-oxidative and anti-inflammatory effects of low-dose proteasome inhibition were identified. In addition, the influence of a genetic deficiency of the immunoproteasomal subunit β5i/LMP7 was investigated in LDLR -/- mice, but this did not affect either early or late atherosclerosis in the mouse model. These studies suggest that although the proteasome could be a potential target for future therapies, more specific targeting of components of the ubiquitin-proteasome system is required to counteract inflammation in a more targeted manner with few side effects. Cardiovascular diseases are particularly dependent on environmental factors such as diet. The intestinal microbiota reacts sensitively to the environment and diet and interacts with the immune system. Many diseases have already been shown to be influenced by the microbiome. The work presented here investigates the role of the microbiome in hypertension. It was shown that hypertensive renal and cardiac damage is aggravated in the absence of a microbiome in germ-free mice, which could indicate the absence of protective bacterial metabolites. In addition, the influence of a high-salt diet on the microbiome was investigated and Lactobacillus was identified as a salt-sensitive intestinal bacterium that regulates TH17-dependent inflammation and blood pressure by producing a metabolite. Finally, in another study, the short-chain fatty acid propionate was identified as a protective bacterial metabolite that protects against hypertensive cardiac damage via partly Treg-dependent mechanisms. In summary, these studies highlight the microbiome as a promising target for organoprotective therapies in hypertension.