Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder characterized by accelerated cardiovascular disease with extensive fibrosis. It is caused by a mutation in LMNA leading to expression of truncated prelamin A (progerin) in the nucleus. To investigate the contribution of the endothelium to cardiovascular HGPS pathology, we generated an endothelium-specific HGPS mouse model with selective endothelial progerin expression. Transgenic mice develop interstitial myocardial and perivascular fibrosis and left ventricular hypertrophy associated with diastolic dysfunction and premature death. Endothelial cells show impaired shear stress response and reduced levels of endothelial nitric oxide synthase (eNOS) and NO. On the molecular level, progerin impairs nucleocytoskeletal coupling in endothelial cells through changes in mechanoresponsive components at the nuclear envelope, increased F-actin/G-actin ratios, and deregulation of mechanoresponsive myocardin-related transcription factor-A (MRTFA). MRTFA binds to the Nos3 promoter and reduces eNOS expression, thereby mediating a profibrotic paracrine response in fibroblasts. MRTFA inhibition rescues eNOS levels and ameliorates the profibrotic effect of endothelial cells in vitro. Although this murine model lacks the key anatomical feature of vascular smooth muscle cell loss seen in HGPS patients, our data show that progerin-induced impairment of mechanosignaling in endothelial cells contributes to excessive fibrosis and cardiovascular disease in HGPS patients.
Highlights
Hutchinson-Gilford progeria syndrome (HGPS) is a rare, progressive, premature aging disease characterized by growth retardation, alopecia, loss of subcutaneous fat, aged-looking skin, bone abnormalities, and osteoporosis [1,2,3]
A hallmark of HGPS is severe atherosclerosis in childhood characterized by left ventricular (LV) diastolic dysfunction associated with LV hypertrophy [4, 5]
Endothelium-specific expression of progerin leads to cardiovascular pathology
Summary
Hutchinson-Gilford progeria syndrome (HGPS) is a rare, progressive, premature aging disease characterized by growth retardation, alopecia, loss of subcutaneous fat, aged-looking skin, bone abnormalities, and osteoporosis [1,2,3]. Cardiovascular features in HGPS include a spectrum of early- to late-stage collagen-rich plaques with a primary vascular pathology of severe vascular smooth muscle cell (VSMC) loss in large arteries [4, 6, 7] and massive fibrosis in the adventitial layer [4], hyaluronan accumulation, and calcification of blood vessels [8]. These changes increase aortic stiffness and cardiac afterload, presumably causing LV hypertrophy and myocardial infarction in patients at a mean age of 14.6 years [9]. Progerin expression impaired nucleocytoskeletal coupling and shear stress response in ECs leading to impaired mechanoresponsive myocardin-related transcription factor A (MRTFA) signaling
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