scholarly journals Lonafarnib improves cardiovascular function and survival in a mouse model of Hutchinson-Gilford Progeria Syndrome

2021 ◽  
Author(s):  
Sae-Il Murtada ◽  
Nicole Mikush ◽  
Molly Wang ◽  
Pengwei Ren ◽  
Yuki Kawamura ◽  
...  
Keyword(s):  
Mouse Model ◽  
Premature Death ◽  
Left Ventricular Diastolic Function ◽  
Detailed Examination ◽  
Left Ventricular ◽  
Arterial Structure ◽  
End Stage ◽  
And Function ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Clinical trials have demonstrated that lonafarnib, a farnesyltransferase inhibitor, extends lifespan in patients afflicted by Hutchinson-Gilford progeria syndrome, a devastating condition that accelerates many characteristics of aging and results in premature death due to cardiovascular sequelae. The US Food and Drug Administration approved ZokinvyTM (lonafarnib) in November 2020 for treating these patients, yet a detailed examination of drug-associated effects on cardiovascular structure, properties, and function has remained wanting. In this paper, we report encouraging outcomes of daily post-weaning treatment with lonafarnib on the composition and biomechanical phenotype of elastic and muscular arteries as well as associated cardiac function in a well-accepted mouse model of progeria that exhibits severe end-stage cardiovascular disease. Lonafarnib resulted in 100% survival of the treated progeria mice to the study end-point (time of 50% survival of untreated mice), with associated improvements in arterial structure and function working together to significantly reduce pulse wave velocity and improve left ventricular diastolic function. By contrast, dual treatment with lonafarnib and rapamycin did not improve outcomes over that achieved with lonafarnib monotherapy.

scholarly journals Gremlin2 Regulates the Differentiation and Function of Cardiac Progenitor Cells via the Notch Signaling Pathway

2018 ◽  
Vol 47 (2) ◽  
pp. 579-589 ◽  
Author(s):  
Wei Li ◽  
Yaojun Lu ◽  
Ruijuan Han ◽  
Qiang Yue ◽  
Xiurong Song ◽  
...  
Keyword(s):  
Mouse Model ◽  
Progenitor Cells ◽  
Left Ventricular ◽  
Cardiac Repair ◽  
Cardiac Progenitor Cells ◽  
Cardiomyocyte Differentiation ◽  
Rt Pcr ◽  
And Function

Background/Aims: The transplantation of cardiac progenitor cells (CPCs) improves neovascularization and left ventricular function after myocardial infarction (MI). The bone morphogenetic protein antagonist Gremlin 2 (Grem2) is required for early cardiac development and cardiomyocyte differentiation. The present study examined the role of Grem2 in CPC differentiation and cardiac repair. Methods: To determine the role of Grem 2 during CPC differentiation, c-Kit+ CPCs were cultured in differentiation medium for different times, and Grem2, Notch1 and Jagged1 expression was determined by RT-PCR and western blotting. Short hairpin RNA was used to silence Grem2 expression, and the expression of cardiomyocyte surface markers was assessed by RT-PCR and immunofluorescence staining. In vivo experiments were performed in a mouse model of left anterior descending coronary artery ligation-induced MI. Results: CPC differentiation upregulated Grem2 expression and activated the Notch1 pathway. Grem2 knockdown inhibited cardiomyocyte differentiation, and this effect was similar to that of Notch1 pathway inhibition in vitro. Jagged1 overexpression rescued the effects of Grem2 silencing. In vivo, Grem2 silencing abolished the protective effects of CPC injection on cardiac fibrosis and function. Conclusions: Grem2 regulates CPC cardiac differentiation by modulating Notch1 signaling. Grem2 enhances the protective effect of CPCs on heart function in a mouse model of MI, suggesting its potential as the rapeutic protein for cardiac repair.

scholarly journals Defective Extracellular Pyrophosphate Metabolism Promotes Vascular Calcification in a Mouse Model of Hutchinson-Gilford Progeria Syndrome That Is Ameliorated on Pyrophosphate Treatment

Circulation ◽  
2013 ◽  
Vol 127 (24) ◽  
pp. 2442-2451 ◽  
Author(s):  
Ricardo Villa-Bellosta ◽  
José Rivera-Torres ◽  
Fernando G. Osorio ◽  
Rebeca Acín-Pérez ◽  
José A. Enriquez ◽  
...  
Keyword(s):  
Mouse Model ◽  
Vascular Calcification ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

scholarly journals Ultrasonic Characteristics of Cardiovascular Changes in Children with Hutchinson–Gilford Progeria Syndrome: A Comparative Study with Normal Children and Aging People

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Xiao-Ni Zhao ◽  
Hong-Ping Song ◽  
Fan Yang ◽  
Dang-Jie Wu ◽  
Wen-Qing Gong ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Older People ◽  
Healthy Volunteers ◽  
Left Ventricular ◽  
Healthy Children ◽  
Elastic Parameters ◽  
Normal Children ◽  
Cardiovascular Changes ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Background. The cardiovascular characteristics of children with Hutchinson-Gilford progeria syndrome (HGPS) remain unclear. The present study is aimed at evaluating the cardiovascular changes with ultrasound examination in children with HGPS and compared these with those in normal children and older people. Methods. Seven HGPS children, 21 age-matched healthy children, and 14 older healthy volunteers were evaluated by three-dimensional echocardiography (including strain analysis) and carotid elasticity examination with the echo-tracking technique. Results. Children with HGPS had higher left ventricular ejection fraction (LVEF) and global longitudinal strain, when compared to older healthy volunteers (P<0.05). However, these parameters were not significantly different, when compared to those in healthy children. Furthermore, children with HGPS had lower average peak times in the left ventricle, when compared with the other two groups. For the structure of the carotid artery detected by ultrasound, the abnormality rates were similar between children with HGPS and older healthy volunteers (83.3% vs. 71.4%). The elastic parameters, elastic modulus, stiffness parameter, and pulsed wave transmittal velocity of children with HGPS were lower, when compared to those in older healthy volunteers (P<0.05), while they were higher with arterial compliance (P>0.05). Furthermore, no significant difference existed among the vascular elastic parameters between HGPS and normal children. Conclusion. HGPS children had impaired left ventricular (LV) synchrony, when compared to normal children, although the difference in LVEF was not statistically significant. Furthermore, the structural abnormality of the carotid artery in HGPS children was similar to that in older people, although the index of elasticity appears to be more favorable. These results suggest that the cardiovascular system in HGPS children differs from natural aging.

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