- Title
- A gut microbiome metabolite paradoxically depresses contractile function while activating mitochondrial respiration
- Creator
- Naghipour, Saba; Fisher, Joshua J.; Perkins, Anthony V.; Peart, Jason N.; Headrick, John P.; Du Toit, Eugene F.
- Relation
- Disease Models & Mechanisms Vol. 16, Issue 5
- Publisher Link
- http://dx.doi.org/10.1242/dmm.049975
- Publisher
- The Company of Biologists
- Resource Type
- journal article
- Date
- 2023
- Description
- Trimethylamine-N-oxide (TMAO) is an end-product of gut microbiome metabolism linked to cardiovascular disease (CVD). However, precise cardiovascular influences of the TMAO concentrations reported in early or severe disease remain to be detailed. We investigated acute effects of TMAO on cardiac contractile, coronary and mitochondrial function. Male C57Bl/6 mouse hearts were Langendorff perfused to assess concentration-dependent effects of TMAO (1-300 µM) on left ventricular (LV) function, coronary flow and select protein expression. Effects of 10 µM and 100 µM TMAO on LV mitochondrial function were examined via respirometry. TMAO at 10-300 μM concentration-dependently depressed LV contractile function, with coronary flow paralleling changes in isovolumic pressure development. Direct coronary effects were evident at >30 µM TMAO in hearts performing minimal isovolumic work, although this response was reduced by >65%. In contrast, exposure to 10 µM or 100 μM TMAO increased mitochondrial complex I, II and maximal respiratory fluxes while appearing to reduce outer membrane integrity. Expression of phosphorylated AMPKα and total GSK-3β declined. Thus, acute exposure of mouse hearts to TMAO levels reported in advanced CVD significantly inhibits cardiac contractility and induces modest coronary constriction while paradoxically overactivating mitochondrial respiration.
- Subject
- cardiovascular disease; contractility; coronary flow; mitochondrial respiration; trimethylamine-N-oxide; SDG 3; Sustainable Development Goals
- Identifier
- http://hdl.handle.net/1959.13/1497276
- Identifier
- uon:54316
- Identifier
- ISSN:1754-8403
- Rights
- © 2023. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
- Language
- eng
- Full Text
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