Lonafarnib improves cardiovascular function and survival in a mouse model of Hutchinson-Gilford progeria syndrome
- Department of Biomedical Engineering, Yale University, United States
- Translational Research Imaging Center, Yale University, United States
- Department of Surgery, Yale University, United States
- Department of Pathology, Yale University, United States
- Vascular Biology and Therapeutics Program, Yale University, United States
- Department of Pediatrics, Hasbro Children's Hospital and Warren Albert Medical School, Brown University, United States
Figures
Figure 1 with 1 supplement
The biomechanical phenotype of the descending thoracic aorta (DTA) worsens progressively in untreated LmnaG609G/G609G progeria (GG) mice relative to age-matched wild-type (WT) littermate mice.
(A) Pressure-diameter responses revealed a progressive structural stiffening in progeria from postnatal day P42 to P100 to P140 to P168 (dark curved arrow). (B) The marked, late-stage aortic …
Figure 1—figure supplement 1
Additional biaxial metrics confirm the progressive worsening of the aortic phenotype.
(A) Similar to Figure 1, except for axial force-stretch responses revealing a progressive structural stiffening (left-ward shift) of the descending thoracic aorta (DTA) in untreated LmnaG609G/G609G …
Figure 2 with 1 supplement
Lonafarnib improves survival and central artery stiffness in progeria mice (GG).
(A) Study design, including untreated progeria mice and progeria mice that were given lonafarnib daily in the soft gel-based chow either from postnatal day P100 to P168, denoted L(P100), or from P21 …
Figure 2—figure supplement 1
Addtional biaxial findings confirm positive effects of lonafarnib on select metrics.
(A–F) Additional biomechanical metrics for the descending thoracic aorta (DTA) for four groups compared at P168: age-matched wild-type littermate controls (WT), untreated progeria (GG), lonafarnib …
Figure 3
Lonafarnib treatment improves the vasoactive function of muscular but not elastic arteries.
(A–B) The vasoconstrictive capacity of the aorta declined progressively in untreated progeria mice to near nonexistent levels by postnatal day P140, which persisted to P168, and lonafarnib treatment …
Figure 4 with 1 supplement
Lonafarnib treatment improves histological features in the descending thoracic aorta (DTA), with the drug given from P21 to P168.
(A) Representative Movat-stained cross-sections with computer-based automatic separation of elastic fibers (black), cell cytoplasm (red), proteoglycans/glycosaminoglycans (blue), and collagen …
Figure 4—figure supplement 1
Similar to Figure 4 in the main text, but showing additional representative Movat pentachrome (MOV) and Alizarin Red (ALZ) stained sections.
(A) Sections of descending thoracic aortas (DTAs) showed marked proteoglycan staining (top row, blue) in progeria vessels (GG) at P168 wherein the elastic laminae were also straightened; note, too, …
Figure 5 with 1 supplement
Similar to Figure 2, except for the second-order branch mesenteric artery in age-matched littermate wild-type (WT) control mice and untreated (GG) and treated (GG + L) progeria mice for lonafarnib administration from either P21 or P100 to P168.n=4–5 per group.
(A-F) Lonafarnib did not improve passive properties. See also Figure 5—figure supplement 1 as well as Source data 1. Note that we did not assess mesenteric artery properties in the lonafarnib plus …
Figure 5—figure supplement 1
Similar to Figure 1, except for the second-order branch mesenteric artery (MA) from age-matched littermate wild-type (WT) control mice and untreated progeria (GG) mice at postnatal days P42, P100, P140, and P168.
Note the progressive decline in both (A–F) passive and (G) active properties in progeria, though neither as dramatic as those for the descending thoracic aorta. n=4–5 per group. See Source data 1 …
Figure 6 with 1 supplement
Lonafarnib improves pulse wave velocity (PWV) and left-ventricular diastolic function but not somatic growth.
Focusing on progeria mice (GG) treated with lonafarnib (GG + L) from P21, (A) there was no improvement in body mass measured at P168 despite 100% survival to 168 of the six mice so treated (noting …
Figure 6—figure supplement 1
Additional findings for rapamycin both alone and in combination with lonafarnib.
Similar to Figure 6 in the main text, except with an emphasis on combination lonafarnib + rapamycin (GG + L + R) treatment of progeria mice (GG) for four different metrics evaluated at postnatal day …
Additional files
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MDAR checklist
- https://cdn.elifesciences.org/articles/82728/elife-82728-mdarchecklist1-v1.docx
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Source data 1
Passive mechanics.
- https://cdn.elifesciences.org/articles/82728/elife-82728-data1-v1.xlsx
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Source data 2
Active mechanics.
- https://cdn.elifesciences.org/articles/82728/elife-82728-data2-v1.xlsx
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Source data 3
Survival information.
- https://cdn.elifesciences.org/articles/82728/elife-82728-data3-v1.xlsx
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Source data 4
Histological information.
- https://cdn.elifesciences.org/articles/82728/elife-82728-data4-v1.xlsx
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Source data 5
Echo data.
- https://cdn.elifesciences.org/articles/82728/elife-82728-data5-v1.xlsx
