Myocardial transcriptomic analysis of diabetic patients with aortic stenosis: key role for mitochondrial calcium signaling.

Autor: Cherpaz M; Laboratoire CarMeN - IRIS Team, INSERM, INRA, Université Claude Bernard Lyon-1, Univ-Lyon, 69500, Bron, France.; Centre d'investigation Clinique, Hospices Civils de Lyon, 69500, Bron, France., Meugnier E; Laboratoire CarMeN - IRIS Team, INSERM, INRA, Université Claude Bernard Lyon-1, Univ-Lyon, 69500, Bron, France., Seillier G; Explorations Fonctionnelles Cardiovasculaires, Hospices Civils de Lyon, 69500, Bron, France., Pozzi M; Chirurgie Cardiaque, Hospices Civils de Lyon, 69500, Bron, France., Pierrard R; Service de Cardiologie, CHU Nord, 42100, Saint-Étienne, France., Leboube S; Explorations Fonctionnelles Cardiovasculaires, Hospices Civils de Lyon, 69500, Bron, France.; Laboratoire CarMeN - IRIS Team, INSERM, INRA, Université Claude Bernard Lyon-1, Univ-Lyon, 69500, Bron, France., Farhat F; Chirurgie Cardiaque, Hospices Civils de Lyon, 69500, Bron, France., Vola M; Chirurgie Cardiaque, Hospices Civils de Lyon, 69500, Bron, France., Obadia JF; Chirurgie Cardiaque, Hospices Civils de Lyon, 69500, Bron, France., Amaz C; Centre d'investigation Clinique, Hospices Civils de Lyon, 69500, Bron, France., Chalabreysse L; Laboratoire d'anatomopathologie, Hospices Civils de Lyon, 69500, Bron, France., May C; Centre d'investigation Clinique, Hospices Civils de Lyon, 69500, Bron, France., Chanon S; Laboratoire CarMeN - IRIS Team, INSERM, INRA, Université Claude Bernard Lyon-1, Univ-Lyon, 69500, Bron, France., Brun C; Laboratoire CarMeN - IRIS Team, INSERM, INRA, Université Claude Bernard Lyon-1, Univ-Lyon, 69500, Bron, France., Givre L; Laboratoire CarMeN - IRIS Team, INSERM, INRA, Université Claude Bernard Lyon-1, Univ-Lyon, 69500, Bron, France., Bidaux G; Laboratoire CarMeN - IRIS Team, INSERM, INRA, Université Claude Bernard Lyon-1, Univ-Lyon, 69500, Bron, France., Mewton N; Laboratoire CarMeN - IRIS Team, INSERM, INRA, Université Claude Bernard Lyon-1, Univ-Lyon, 69500, Bron, France.; Centre d'investigation Clinique, Hospices Civils de Lyon, 69500, Bron, France., Derumeaux G; Explorations Fonctionnelles Cardiovasculaires, Hospices Civils de Lyon, 69500, Bron, France.; INSERM U955, Université Paris-Est Créteil, Créteil, France.; Department of Physiology, AP-HP, Henri Mondor Hospital, FHU SENEC, Créteil, France., Bergerot C; Explorations Fonctionnelles Cardiovasculaires, Hospices Civils de Lyon, 69500, Bron, France.; Laboratoire CarMeN - IRIS Team, INSERM, INRA, Université Claude Bernard Lyon-1, Univ-Lyon, 69500, Bron, France., Paillard M; Laboratoire CarMeN - IRIS Team, INSERM, INRA, Université Claude Bernard Lyon-1, Univ-Lyon, 69500, Bron, France. melanie.paillard@univ-lyon1.fr., Thibault H; Explorations Fonctionnelles Cardiovasculaires, Hospices Civils de Lyon, 69500, Bron, France. helene.thibault@chu-lyon.fr.; Laboratoire CarMeN - IRIS Team, INSERM, INRA, Université Claude Bernard Lyon-1, Univ-Lyon, 69500, Bron, France. helene.thibault@chu-lyon.fr.
Jazyk: angličtina
Zdroj: Cardiovascular diabetology [Cardiovasc Diabetol] 2024 Jul 08; Vol. 23 (1), pp. 239. Date of Electronic Publication: 2024 Jul 08.
DOI: 10.1186/s12933-024-02329-5
Abstrakt: Background: Type 2 diabetes (T2D) is a frequent comorbidity encountered in patients with severe aortic stenosis (AS), leading to an adverse left ventricular (LV) remodeling and dysfunction. Metabolic alterations have been suggested as contributors of the deleterious effect of T2D on LV remodeling and function in patients with severe AS, but so far, the underlying mechanisms remain unclear. Mitochondria play a central role in the regulation of cardiac energy metabolism.
Objectives: We aimed to explore the mitochondrial alterations associated with the deleterious effect of T2D on LV remodeling and function in patients with AS, preserved ejection fraction, and no additional heart disease.
Methods: We combined an in-depth clinical, biological and echocardiography phenotype of patients with severe AS, with (n = 34) or without (n = 50) T2D, referred for a valve replacement, with transcriptomic and histological analyses of an intra-operative myocardial LV biopsy.
Results: T2D patients had similar AS severity but displayed worse cardiac remodeling, systolic and diastolic function than non-diabetics. RNAseq analysis identified 1029 significantly differentially expressed genes. Functional enrichment analysis revealed several T2D-specific upregulated pathways despite comorbidity adjustment, gathering regulation of inflammation, extracellular matrix organization, endothelial function/angiogenesis, and adaptation to cardiac hypertrophy. Downregulated gene sets independently associated with T2D were related to mitochondrial respiratory chain organization/function and mitochondrial organization. Generation of causal networks suggested a reduced Ca 2+ signaling up to the mitochondria, with the measured gene remodeling of the mitochondrial Ca 2+ uniporter in favor of enhanced uptake. Histological analyses supported a greater cardiomyocyte hypertrophy and a decreased proximity between the mitochondrial VDAC porin and the reticular IP3-receptor in T2D.
Conclusions: Our data support a crucial role for mitochondrial Ca 2+ signaling in T2D-induced cardiac dysfunction in severe AS patients, from a structural reticulum-mitochondria Ca 2+ uncoupling to a mitochondrial gene remodeling. Thus, our findings open a new therapeutic avenue to be tested in animal models and further human cardiac biopsies in order to propose new treatments for T2D patients suffering from AS.
Trial Registration: URL: https://www.
Clinicaltrials: gov ; Unique Identifier: NCT01862237.
(© 2024. The Author(s).)
Databáze: MEDLINE
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