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Naghipour 2023 Dis Model Mech

From Bioblast
Publications in the MiPMap
Naghipour S, Fisher JJ, Perkins AV, Peart JN, Headrick JP, Du Toit EF (2023) Trimethylamine-N-oxide paradoxically depresses contractile function while activating mitochondrial respiration in mouse hearts.

» Dis Model Mech 16:dmm049975. PMID: 37078591 Open Access

Naghipour Saba, Fisher Joshua J, Perkins Anthony V, Peart Jason N, Headrick John P, Du Toit Eugene F (2023) Dis Model Mech

Abstract: 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 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, though this response was reduced by >65%. In contrast, exposure to 10 or 100 µM TMAO increased mitochondrial complex I, II and maximal respiratory fluxes while appearing to reduce outer membrane integrity. Expression of phospho-AMPKα and total GSK-3β declined. Acute exposure to TMAO levels reported in advanced CVD significantly inhibits cardiac contractility and induces modest coronary constriction while paradoxically over-activating mitochondrial respiration. Keywords: Cardiovascular disease, Contractility, Coronary flow, Mitochondrial respiration, Trimethylamine-N-oxide Bioblast editor: Plangger M O2k-Network Lab: AU Southport Peart J

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