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Circulation. 2018 Dec 4. doi: 10.1161/CIRCULATIONAHA.118.036652. [Epub ahead of print]

The Short-Chain Fatty Acid Propionate Protects from Hypertensive Cardiovascular Damage.

Author information

1
ECRC, Experimental and Clinical Research Center, a cooperation of Charite-Universitätsmedizin Berlin and Max Delbruck Center for Molecular Medicine, GERMANY.
2
AG Mueller/Dechend, Experimental and Clinical Research Center, a joint cooperation between the Max-DelbrÃ1/4ck Center for Molecular Medicine and the CharitÃ{copyright, serif} Medical Faculty, GERMANY.
3
Nephrology, University Hospital, Heinrich-Heine-University, GERMANY.
4
Institute of Pharmacology and Clinical Pharmacology, University Hospital Düsseldorf, GERMANY.
5
Department of Hypertension-caused end-organ damage, Experimental and Clinical Research Center a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, GERMANY.
6
Experimental and Clinical Research Center a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Charité, GERMANY.
7
Berlin Institute of Health, GERMANY.
8
Experimental and Clinical Research Center, a cooperation of Charite-Universitätsmedizin Berlin and Max Delbruck Center for Molecular Medicine, GERMANY.
9
ECRC, Experimental and Clinical Research Center , Lindenberger Weg 80, GERMANY.
10
Experimental and Clinical Research Center, Max-Delbrueck Center for Molecular Medicine, GERMANY.
11
Experimental Nephrology, University Hospital, Heinrich-Heine-University, GERMANY.
12
University of Muenster, Institute of Physiology II, GERMANY.
13
Institute of Physiology, University of Luebeck, GERMANY.
14
Institute of Pharmacology and Clinical Pharmacology, University Hospital Düsseldorf, Heinrich-Heine University of Düsseldorf, GERMANY.
15
Molecular Cardiology, University Medicine Greifswald, GERMANY.
16
Max Delbruck Center for Molecular Medicine in the Helmholtz Association, GERMANY.
17
Medical Clinic for Nephrology and Internal Intensive Care, Charité Campus Virchow Klinikum, GERMANY.
18
Nazarbayev Univeristy, KAZAKHSTAN.
19
Center for Life Sciences, Nazarbayev University, KAZAKHSTAN.
20
Medizinische Klinik mit Schwerpunkt Nephrologie und Internistische Intensivmedizin, Charite-Universitätsmedizin Berlin, GERMANY.
21
HELIOS Klinikum Berlin, Department of Cardiology and Nephrology, Experimental and Clinical Research Center, GERMANY.
22
Department of Nephrology, Heinrich-Heine-University, GERMANY.
23
Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Charité-Universitätsmedizin Berlin, GERMANY.

Abstract

BACKGROUND:

Arterial hypertension and its organ sequelae show characteristics of T cell mediated inflammatory diseases. Experimental anti-inflammatory therapies have been shown to ameliorate hypertensive end-organ damage. Recently, the CANTOS study targeting interleukin-1β demonstrated that anti-inflammatory therapy reduces cardiovascular risk. The gut microbiome plays pivotal role in immune homeostasis and cardiovascular health. Short-chain fatty acids (SCFA) are produced from dietary fiber by gut bacteria and affect host immune homeostasis. Here, we investigated effects of the SCFA propionate in two different mouse models of hypertensive cardiovascular damage.

METHODS:

To investigate the effect of SCFA on hypertensive cardiac damage and atherosclerosis, wild-type NMRI (WT) or ApoE-/- deficient mice received propionate (200mM) or control in the drinking water. To induce hypertension, WT mice were infused with Angiotensin (Ang)II (1.44mg/kg/d s.c.) for 14 days. To accelerate the development of atherosclerosis, ApoE-/- mice were infused with AngII (0.72mg/kg/d s.c.) for 28 days. Cardiac damage and atherosclerosis were assessed using histology, echocardiography, in vivo electrophysiology, immunofluorescence, and flow cytometry. Blood pressure was measured by radiotelemetry. Regulatory T cell (Treg) depletion using PC61 antibody was used to examine the mode of action of propionate.

RESULTS:

Propionate significantly attenuated cardiac hypertrophy, fibrosis, vascular dysfunction, and hypertension in both models. Susceptibility to cardiac ventricular arrhythmias was significantly reduced in propionate-treated AngII-infused WT mice. Aortic atherosclerotic lesion area was significantly decreased in propionate-treated ApoE-/-. Systemic inflammation was mitigated by propionate treatment, quantified as a reduction in splenic effector memory T cell frequencies and splenic T helper 17 cells in both models, and a decrease in local cardiac immune cell infiltration in WT mice. Cardioprotective effects of propionate were abrogated in Treg-depleted AngII-infused mice, suggesting the effect is Treg-dependent.

CONCLUSIONS:

Our data emphasize an immune-modulatory role of SCFAs and their importance for cardiovascular health. The data suggest that lifestyle modifications leading to augmented SCFA production could be a beneficial non-pharmacological preventive strategy for patients with hypertensive cardiovascular disease.

KEYWORDS:

Bacterial Metabolites; Microbiome; Regulatory T cells; Short-chain fatty acids; Th17 cells

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