The cold receptor TRPM8, a new target against the aggravating effects of metabolic syndrome in heart failure with preserved ejection fraction

Abstract

Heart failure with preserved ejection fraction (HFpEF) has nowadays become a major public health issue worldwide. HFpEF is usually associated with metabolic syndrome (MS) such as type II diabetes. A growing attention has been shed on Δ9-desaturase (SCD1), the bottleneck enzyme in the mono-desaturation of fatty acids. Indeed, SCD1 controls the balance between inflammation regulated by saturated lipids and weight gain regulated by unsaturated lipids. Targeting SCD1 looks an attractive strategy in limiting the deleterious effects of the MS and HFpEF. In our recent work, we found that isoforms of the cold receptor, TRPM8, control SCD1 expression in epithelial cells and we wonder if this mechanism could be used to prevent HFpEF. (1) To identify the mechanisms by which TRPM8 regulates SCD1 in cell models. (2) Study whether genetic or pharmacological inhibition of TRPM8 prevents MS and HFpEF. Epithelial cells were transfected by siRNA targeting TRPM8 then SCD1 expression was assessed by western blot. Golgi expansion was studied by immunofluorescence after transfection with SCD1-YFP. In vivo, we will finish the metabolic and cardiac phenotype of TRPM8-/- mice. Then we plan to feed wild type and TRPM8-/- mice with chow or high fat high sucrose diet for 16 weeks. Endurance test, blood chemistry, echocardiography will be done to assess development of HFpEF. Lipidomic analysis will assess changes in lipid profile between the 2 groups and inflammation will be assessed by ELISA and flow cytometry. In vitro studies: SCD1 expression has transiently increased upon TRPM8 knockdown in epithelial cells. This was associated with an increase in unsaturated lipids (MUFAs and PUFAs) that led to increase in the Golgi surface area and impairment of vesicles trafficking. Golgi expansion could be suppressed by SCD1 knockdown. In vivo studies, phenotyping the TRPM8-/- mouse line showed a lean phenotype, with modifications in lipid metabolism in liver characterized by a 50% decrease in SCD1 level and resistance to adipogenesis under a short-term high fat diet. Besides, TRPM8-/- mice were less fat and had a heavier heart. TRPM8 regulates the expression of SCD1, which is dysregulated in metabolic disorders. We aim to exploit this mechanism and study if TRPM8 inhibition can prevent MS and HFpEF.