Identification of common cardiometabolic alterations and deregulated pathways in mouse and pig models of aging

Fanjul, Víctor; Jorge, Inmaculada; Camafeita, Emilio; Macías, Álvaro; González‐Gómez, Cristina; Barettino, Ana; Dorado, Beatriz; Andrés‐Manzano, María Jesús; Rivera‐Torres, José; Vázquez, Jesús; López-Otı́n, Carlos; Andrés, Vicente

doi:10.1111/acel.13203

Cited by 12 publications

(15 citation statements)

References 70 publications

(103 reference statements)

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“…Among cardiovascular alterations, our studies in HGPS patients 9 and progeroid Zmpste24 −/− mice, 9 Lmna G609G/G609G (G609G) 10 mice and LMNA 1824 C > T minipigs 11 revealed defective cardiac repolarization as a common feature of progeria. Specifically, HGPS patients showed progressive overt ST segment alterations as they age, which were also present in progeroid Zmpste24 −/− mice 9 and G609G mice.…”

Section: Introductionmentioning

confidence: 78%

“…We previously reported electrophysiological defects in HGPS animal models, including progeroid Zmptse −/− mice, 9 G609G mice, 10 and LMNA 1824 C>T knockin minipigs. 11 Here, we also found cardiac electrophysiological alterations in G609G mice, including bradycardia, prolonged PR and QT intervals, and Cx43 mislocalization.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, HGPS patients showed progressive overt ST segment alterations as they age, which were also present in progeroid Zmpste24 −/− mice 9 and G609G mice. 10 More careful sequential follow-up also showed that conduction abnormalities and bradycardia are present at late stages of the disease in both mice and pig models of progeria. 9–11 However, the mechanisms by which progerin expression causes these and other cardiac alterations remain largely unknown.…”

Section: Introductionmentioning

confidence: 95%

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Paclitaxel mitigates structural alterations and cardiac conduction system defects in a mouse model of Hutchinson–Gilford progeria syndrome

Macías

Díaz-Larrosa

Blanco

et al. 2021

Cardiovascular Research

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Aims Hutchinson-Gilford progeria syndrome (HGPS) is an ultrarare laminopathy caused by expression of progerin, a lamin A variant, also present at low levels in non-HGPS individuals. HGPS patients age and die prematurely, predominantly from cardiovascular complications. Progerin-induced cardiac repolarization defects have been described previously, although the underlying mechanisms are unknown. Methods and Results We conducted studies in heart tissue from progerin-expressing LmnaG609G/G609G (G609G) mice, including microscopy, intracellular calcium dynamics, patch-clamping, in vivo magnetic resonance imaging, and electrocardiography. Mouse G609G cardiomyocytes showed tubulin-cytoskeleton disorganization, t-tubular system disruption, sarcomere shortening, altered excitation-contraction coupling, and reductions in ventricular thickening and cardiac index. G609G mice exhibited severe bradycardia, and significant alterations of atrio-ventricular conduction and repolarization. Most importantly, 50% of G609G mice had altered heart rate variability, and sinoatrial block, both significant signs of premature cardiac aging. G609G cardiomyocytes had electrophysiological alterations which result in an elevated action potential plateau and early afterdepolarization bursting, reflecting slower sodium current inactivation and long Ca+2 transient duration, which may also help explain the mild QT prolongation in some HGPS patients. Chronic treatment with low-dose paclitaxel ameliorated structural and functional alterations in G609G hearts. Conclusions Our results demonstrate that tubulin-cytoskeleton disorganization in progerin-expressing cardiomyocytes causes structural, cardiac conduction and excitation-contraction coupling defects, all of which can be partially corrected by chronic treatment with low-dose of paclitaxel.

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Section: Introductionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

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Paclitaxel mitigates structural alterations and cardiac conduction system defects in a mouse model of Hutchinson–Gilford progeria syndrome

Macías

Díaz-Larrosa

Blanco

et al. 2021

Cardiovascular Research

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“…Using this model, these authors provided the first in vivo evidence that antisense morpholino-based therapy to prevent the pathogenic Lmna splicing might be viable for HGPS. Homozygous Lmna G609G/G609G mice express progerin, lamin C, and residual levels of lamin A and show many HGPS features, including failure to thrive, bone defects, loss of fat deposits, bradycardia, prolonged QRS waves (indicating altered heart ventricular depolarization), and premature death [ 45 , 49 , 52 ]. Lmna G609G/G609G cardiomyocytes have structural, conduction, and excitation-contraction coupling defects, all of which can be partially corrected by chronic treatment with the microtubule-stabilizing drug paclitaxel [ 49 ].…”

Section: The Cardiovascular Phenotype In Animal Models Of Hgpsmentioning

confidence: 99%

“…1 , Y qo in [ 39 ], N in [ 35 , 38 ]. 2 , Y in [ 52 ] (n = 12–16 mice), N in [ 45 ] (n = 4 mice). *, results obtained in 16-week-old mice; however, 26-week-old Apoe −/− Lmna LCS/LCS SM22αCre mice present modest but significant cardiac electrical anomalies [ 53 ].…”

Section: Figurementioning

confidence: 99%

Molecular and Cellular Mechanisms Driving Cardiovascular Disease in Hutchinson-Gilford Progeria Syndrome: Lessons Learned from Animal Models

Benedicto

Dorado

Andrés

2021

Cells

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Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease that recapitulates many symptoms of physiological aging and precipitates death. Patients develop severe vascular alterations, mainly massive vascular smooth muscle cell loss, vessel stiffening, calcification, fibrosis, and generalized atherosclerosis, as well as electrical, structural, and functional anomalies in the heart. As a result, most HGPS patients die of myocardial infarction, heart failure, or stroke typically during the first or second decade of life. No cure exists for HGPS, and therefore it is of the utmost importance to define the mechanisms that control disease progression in order to develop new treatments to improve the life quality of patients and extend their lifespan. Since the discovery of the HGPS-causing mutation, several animal models have been generated to study multiple aspects of the syndrome and to analyze the contribution of different cell types to the acquisition of the HGPS-associated cardiovascular phenotype. This review discusses current knowledge about cardiovascular features in HGPS patients and animal models and the molecular and cellular mechanisms through which progerin causes cardiovascular disease.

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

et al. 2023

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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 LmnaG609G/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 KV7 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 KV7 channels as a candidate target for the treatment of HGPS.

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Identification of common cardiometabolic alterations and deregulated pathways in mouse and pig models of aging

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 12 publications

References 70 publications

Paclitaxel mitigates structural alterations and cardiac conduction system defects in a mouse model of Hutchinson–Gilford progeria syndrome

Paclitaxel mitigates structural alterations and cardiac conduction system defects in a mouse model of Hutchinson–Gilford progeria syndrome

Molecular and Cellular Mechanisms Driving Cardiovascular Disease in Hutchinson-Gilford Progeria Syndrome: Lessons Learned from Animal Models

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

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