Progerin Expression during Normal Closure of the Human Ductus Arteriosus: A Case of Premature Ageing?
The ductus arteriosus (DA) is a fetal vessel bypassing the still nonfunctional lungs. Closure of the DA at birth is essential for the transition from a fetal to a neonatal circulation. This closing process begins with a physiological contraction followed by definitive anatomical closure. The latter process starts already before birth by development of intimal thickening followed after birth by degeneration of the inner media, including cytolytic necrosis and apoptosis. The DA will remain patent when there is insufficient maturation in prematurely born babies or when there is a structural abnormality as seen in persistent DA (PDA). The histological changes during normal DA closure resemble the features seen in the premature ageing vessels in children with the Hutchinson progeria syndrome. The latter syndrome is caused by a mutation in the lamin A/C gene resulting in accumulation of the progerin splice variant. We studied human DA biopsies from the fetal to the neonatal period to investigate whether lamin A/C and progerin might be involved in the DA closure process. The results show an increase in the intima and inner media of progerin in the normal neonatal DA, while expression of lamin A/C is diminished. In the non-closing aorta, the fetal DA and the PDA, no or hardly any progerin expression was found. We postulate that the lamin A/C to progerin balance is important during normal anatomical closure of the DA presenting a unique case of physiological premature vascular ageing.
KeywordsLamin A/C Progerin Atherosclerosis Apoptosis Vascular biology Persistent ductus arteriosus
34.2 Material and Methods
Following aortic arch reconstruction and surgical closure of the DA, a biopsy specimen of human neonatal DA (n = 16) and adjoining descending aorta (n = 2) was obtained. The fetal DA (one of 14 weeks’ and one of 18 weeks’ gestation) was acquired from postmortem fetal specimen after legal or spontaneous abortion. One biopsy specimen was obtained from a 2-year-old child with PDA. Details on sectioning, fixation, and immunohistochemistry have been described as well as the technique for RNA isolation and RT-PCR reactions .
Normal ductal closure is regulated by many molecular pathways . In our study, we introduced for the first time a role for lamina A/C and progerin . This observation was triggered by the histopathology found in the vessel wall of young adolescents with the HGPS , in which premature atherosclerosis was observed. The physiological development of prenatal intimal thickening and the development of cytolytic necrosis in the DA showing contractions after birth mimic the degenerative changes seen in the HGPS. Alterations in the farnesylation process can be the cause of accumulation of progerin at the nuclear membrane. This process is associated with the initiation of apoptosis in these progerin-expressing cells , being characteristic for degeneration in the DA media . The cause for progerin increase in the closing DA needs further investigation, but it is known that alternative splicing is affected by oxidative stress  which is activated during normal DA closure . Accumulation of reactive oxygen species has also been observed during vascular ageing  in which an increase of progerin has been described in the smooth mus cle cells of the coronary vessels of elderly persons as well as a gradual increase of progerin-expressing cells in other vessels with upclimbing age [7, 10]. It is noteworthy that the non-closing PDA, although only one case has been studied, and the aorta did not show progerin increase in the neonatal stage. This aspect needs further study as in families with bicuspid aortic valve (BAV) a correlation with PDA  has been reported. Unpublished data from our group show a diminished progerin expression in the dilated ascending aorta in BAV as compared to dilation of the aorta in tricuspid valves. The latter shows an increase in progerin indicative of advanced ageing.
Potentially, ductal closure based on increased progerin expression could lead to fetal demise in HGPS; this has, however, not been reported.
34.5 Future Directions and Clinical Applications
Further research is necessary to elucidate the role of the lamin A/C to progerin balance in vascular pathology, ageing, and the unique observation in selective DA closure at birth.
Clinical applications might be related to the use of farnesyltransferase inhibitors which may prevent onset and progression induced by the accumulation of progerin . It cannot be excluded that inhibition of physiological progerin expression might prevent anatomical closure of the DA, which can be relevant in ductus-dependent congenital heart disease.
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