Coronary and carotid artery dysfunction and KV7 overexpression in a mouse model of Hutchinson-Gilford progeria syndrome

• Published in: GeroScience Vol. 46; no. 1; pp. 867 - 884
• Main Authors: Macías, Álvaro, Nevado, Rosa M., González-Gómez, Cristina, Gonzalo, Pilar, Andrés-Manzano, María Jesús, Dorado, Beatriz, Benedicto, Ignacio, Andrés, Vicente
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.02.2024; Springer Nature B.V
• Subjects: Aorta; Biomedical and Life Sciences; Carotid arteries; Carotid artery; Cell Biology; Cerebral infarction; Coronary artery; Gene expression; Genetic disorders; Geriatrics/Gerontology; Heart; Hypoxia; Hypoxia-inducible factor 1a; Hypoxia-inducible factors; Life Sciences; Molecular Medicine; Myocardial infarction; Original; Original Article; Potassium channels (voltage-gated); Progeria; Smooth muscle; Stenosis; Vascularization; Hypoxia; Hutchinson-Gilford progeria syndrome; Ion channels; Carotid artery; Vascular smooth muscle cells; Coronary artery
• ISSN: 2509-2723; 2509-2715; 2509-2723
• DOI: 10.1007/s11357-023-00808-3

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disease caused by expression of progerin, a lamin A variant that is also expressed at low levels in non-HGPS individuals. Although HGPS patients die predominantly from myocardial infarction and stroke, the mechanisms that provoke pathological alterations in the coronary and cerebral arteries in HGPS remain ill defined. Here, we assessed vascular function in the coronary arteries (CorAs) and carotid arteries (CarAs) of progerin-expressing Lmna G609G/G609G mice (G609G), both in resting conditions and after hypoxic stimulus. Wire myography, pharmacological screening, and gene expression studies demonstrated vascular atony and stenosis, as well as other functional alterations in progeroid CorAs and CarAs and aorta. These defects were associated with loss of vascular smooth muscle cells and overexpression of the K V 7 family of voltage-dependent potassium channels. Compared with wild-type controls, G609G mice showed reduced median survival upon chronic isoproterenol exposure, a baseline state of chronic cardiac hypoxia characterized by overexpression of hypoxia-inducible factor 1α and 3α genes, and increased cardiac vascularization. Our results shed light on the mechanisms underlying progerin-induced coronary and carotid artery disease and identify K V 7 channels as a candidate target for the treatment of HGPS.