Thrombosis in the Coronary Microvasculature Impairs Cardiac Relaxation and Induces Diastolic Dysfunction.
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EN
Article de revue
Ce document a été publié dans
Arteriosclerosis, Thrombosis, and Vascular Biology. 2024-01-01, vol. 44, n° 1, p. e1-e18
Résumé en anglais
Heart failure with preserved ejection fraction is proposed to be caused by endothelial dysfunction in cardiac microvessels. Our goal was to identify molecular and cellular mechanisms underlying the development of cardiac ...Lire la suite >
Heart failure with preserved ejection fraction is proposed to be caused by endothelial dysfunction in cardiac microvessels. Our goal was to identify molecular and cellular mechanisms underlying the development of cardiac microvessel disease and diastolic dysfunction in the setting of type 2 diabetes. We used (leptin receptor-deficient) female mice as a model of type 2 diabetes and heart failure with preserved ejection fraction and identified Hhipl1 (hedgehog interacting protein-like 1), which encodes for a decoy receptor for HH (hedgehog) ligands as a gene upregulated in the cardiac vascular fraction of diseased mice. We then used (desert HH)-deficient mice to investigate the functional consequences of impaired HH signaling in the adult heart. We found that -deficient mice displayed increased end-diastolic pressure while left ventricular ejection fraction was comparable to that of control mice. This phenotype was associated with a reduced exercise tolerance in the treadmill test, suggesting that -deficient mice do present heart failure. At molecular and cellular levels, impaired cardiac relaxation in mice was associated with a significantly decreased PLN (phospholamban) phosphorylation on Thr17 (threonine 17) and an alteration of sarcomeric shortening ex vivo. Besides, as expected, -deficient mice exhibited phenotypic changes in their cardiac microvessels including a prominent prothrombotic phenotype. Importantly, aspirin therapy prevented the occurrence of both diastolic dysfunction and exercise intolerance in these mice. To confirm the critical role of thrombosis in the pathophysiology of diastolic dysfunction, we verified also displays increased cardiac microvessel thrombosis. Moreover, consistently, with -deficient mice, we found that aspirin treatment decreased end-diastolic pressure and improved exercise tolerance in mice. Altogether, these results demonstrate that microvessel thrombosis may participate in the pathophysiology of heart failure with preserved ejection fraction.< Réduire
Mots clés
article recherche
Mots clés en anglais
Animals
Female
Mice
Ventricular Function
Left
Stroke Volume
Diabetes Mellitus
Type 2
Ventricular Dysfunction
Left
Hedgehog Proteins
Cardiomyopathies
Heart Failure
Microvessels
Thrombosis
Aspirin
Unités de recherche