Dataset Information

Arterial stiffness and cardiac dysfunction in Hutchinson-Gilford Progeria Syndrome corrected by inhibition of lysyl oxidase.

ABSTRACT: Arterial stiffening and cardiac dysfunction are hallmarks of premature aging in Hutchinson-Gilford Progeria Syndrome (HGPS), but the molecular regulators remain unknown. Here, we show that the LaminA^G609G mouse model of HGPS recapitulates the premature arterial stiffening and early diastolic dysfunction seen in human HGPS. Lysyl oxidase (LOX) is up-regulated in the arteries of these mice, and treatment with the LOX inhibitor, β-aminopropionitrile, improves arterial mechanics and cardiac function. Genome-wide and mechanistic analysis revealed reduced expression of the LOX-regulator, miR-145, in HGPS arteries, and forced expression of miR-145 restores normal LOX gene expression in HGPS smooth muscle cells. LOX abundance is also increased in the carotid arteries of aged wild-type mice, but its spatial expression differs from HGPS and its up-regulation is independent of changes in miR-145 abundance. Our results show that miR-145 is selectively misregulated in HGPS and that the consequent up-regulation of LOX is causal for premature arterial stiffening and cardiac dysfunction.

SUBMITTER: von Kleeck R

PROVIDER: S-EPMC8008950 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Arterial stiffness and cardiac dysfunction in Hutchinson-Gilford Progeria Syndrome corrected by inhibition of lysyl oxidase.

von Kleeck Ryan R Roberts Emilia E Castagnino Paola P Bruun Kyle K Brankovic Sonja A SA Hawthorne Elizabeth A EA Xu Tina T Tobias John W JW Assoian Richard K RK

Life science alliance 20210309 5

Arterial stiffening and cardiac dysfunction are hallmarks of premature aging in Hutchinson-Gilford Progeria Syndrome (HGPS), but the molecular regulators remain unknown. Here, we show that the LaminA<sup>G609G</sup> mouse model of HGPS recapitulates the premature arterial stiffening and early diastolic dysfunction seen in human HGPS. Lysyl oxidase (LOX) is up-regulated in the arteries of these mice, and treatment with the LOX inhibitor, β-aminopropionitrile, improves arterial mechanics and cardi ...[more]

PMID: 33687998

Similar Datasets

Project description:Importance:Hutchinson-Gilford progeria syndrome (HGPS) is an ultrarare disorder associated with premature death due to cardiovascular events during the second decade of life. However, because of its rarity (107 identified living patients), the natural history of cardiac disease remains uncharacterized. Therefore, meaningful cardiac end points for clinical trials have been difficult to establish. Objective:To examine the course of appearance of cardiac abnormalities in patients with HGPS to identify meaningful cardiac end points for use in future clinical trials. Design, Setting, and Participants:In this prospective, cross-sectional, observational study, 27 consecutive patients with clinically and genetically confirmed classic HGPS were evaluated at a single center for 1 visit from July 1, 2014, through February 29, 2016, before initiation of treatment. Exposure:Classic HGPS. Main Outcomes and Measures:Echocardiography was used to assess ventricular and valve function using standard techniques. Diastolic left ventricular (LV) function was assessed using tissue Doppler imaging. Previously published normative data were used to adjust findings to age and body size. Results:This study included 27 patients (median age, 5.6 years; age range, 2-17 years; 15 [56%] male). Among echocardiographic indicators, LV diastolic dysfunction, defined as a tissue Doppler septal or lateral early velocity z score less than -2, was the most prevalent abnormality, seen in 16 patients (59%). Diastolic dysfunction was seen in all age groups, and its prevalence increased with age, mirroring findings seen during normal aging. Indicators of LV diastolic function were more abnormal in older patients. The z scores for lateral and septal early velocities were lower (r = -0.77, P < .001; and r = -0.66, P < .001, respectively), whereas those for the ratio of early mitral inflow velocity to early diastolic tissue Doppler myocardial velocity were higher (r = 0.80, P < .001; and r = 0.72, P < .001, respectively) in older patients. Other echocardiographic findings, including LV hypertrophy, LV systolic dysfunction, and valve disease, were less prevalent in the first decade and were seen more frequently in the second decade. Conclusions and Relevance:In this largest-to-date cohort of patients with HGPS, LV diastolic dysfunction was the most prevalent echocardiographic abnormality and its prevalence increased with aging. Echocardiographic indicators of LV diastolic function may be useful end points in future clinical trials in this patient population.

Project description:Children with Hutchinson-Gilford progeria syndrome (HGPS) succumb to myocardial infarction and stroke in their teen years. Endothelial dysfunction is an early event in more common forms of atherosclerosis. Endothelial pathobiology may contribute to HGPS, but a comprehensive characterization of endothelial function in HGPS has not been performed. iPSCs derived from fibroblasts of HGPS patients or unaffected relatives were differentiated into endothelial cells (ECs). Immunofluorescent signal of the pluripotent stem cell markers SSEA4, Oct4, Sox2 and TRAI-60 was similar in HGPS or control iPSCs. Following the differentiation, FACS analysis and immunocytochemistry for CD31 and CD144 revealed a smaller percentage of ECs from HGPS iPSCs. Immunostaining for Lamin A revealed nuclear dysmorphology in HGPS iPSC-ECs. Furthermore, these cells were significantly larger and rounded, and they proliferated less, features which are typical of senescent endothelial cells. HGPS iPSC-ECs manifested less Dil-Ac-LDL uptake; less DAF-2DA staining for nitric oxide generation and formed fewer networks in matrigel in vitro. In immunodeficient mice injected with iPSC-ECs, HGPS iPSC-ECs generated a sparser vascular network compared to the control, with reduced capillary number. Telomere length (T/S ratio) of HGPS iPSC-EC was reduced as assessed by mmqPCR. iPSC-ECs derived from HGPS patients have dysmorphic appearance, abnormal nuclear morphology, shortened telomeres, reduced replicative capacity and impaired functions in vitro and in vivo. Targeting the endothelial abnormality in patients with HGPS may provide a new therapeutic avenue for the treatment of this condition. Abbreviations: HGPS: Hutchinson-Gilford progeria syndrome; ZMPSTE24: Zinc metallopeptidase STE24; FTI: Farnesyltransferase inhibitors; VSMCs: Vascular smooth muscle cells; iPSC: Induced pluripotent stem cells; EC: Endothelial cells; hTERT: Human telomerase reverse transcriptase; VEGF: vascular endothelial growth factor; DAF-FM DA: 3-Amino, 4-aminomethyl-2',7'-difluorofluorescein diacetate; BMP4: Bone Morphogenetic Protein 4; mmqPCR: mono chrome multiplex PCR; SCG: single-copy gene; CSI: Cell shape index.

Dataset Information

Arterial stiffness and cardiac dysfunction in Hutchinson-Gilford Progeria Syndrome corrected by inhibition of lysyl oxidase.

Publications

Arterial stiffness and cardiac dysfunction in Hutchinson-Gilford Progeria Syndrome corrected by inhibition of lysyl oxidase.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets