In:
Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 142, No. Suppl_3 ( 2020-11-17)
Abstract:
Introduction: In contrast to other adult tissues myocardium cannot be sufficiently regenerated following significant myocardial infarction (MI). Efficient cardiac regeneration was demonstrated in neonatal mouse myocardial injury models. Similar observations were reported in other neonatal mammals including newborn human babies suffering from MI. The mechanisms of neonatal mammalian cardiac regeneration remain unclear. Here we show the crucial role of IGF1R which was unraveled in a time-course transcriptome analysis of neonatal mouse hearts. Methods: IGF1R was specifically knocked-down (KD) in cardiomyocytes of wildtype postnatal day one (P1) mice using adeno-associated virus (rAAV9) delivered shRNAmirs. KD of Renilla served as control (REN-CTRL). 5x10 13 viral genomes per kg bodyweight were injected intrathoracally. Three batches of rAAV9 with different shRNAmirs were used for the IGF1R-KD groups. Viral transduction was confirmed by bioluminescence imaging on luciferase containing rAAV9 copies and by immunofluorescence staining of rAAV9 delivered GFP reporter. KD efficiency was confirmed in vitro using a retrovirus system and in vivo. On P2 mice underwent either left anterior descending artery (LAD) ligation for induction of MI or SHAM surgery. Cardiac function was subsequently assessed by echocardiography 1 day post injury (dpi) and 21 dpi. Thereafter, hearts were harvested and left ventricular fibrosis was analyzed histologically. Results: LAD ligation resulted in significant MI in both, IGF1R-KD and REN-CTRL, LAD groups as proven by a markedly reduced ejection fraction (EF) 1 dpi. Importantly, 21 dpi IGF1R-KD and REN-CTRL SHAM groups displayed normal cardiac function proving no effect on neonatal cardiac growth and development of only KD of IGF1R without LAD ligation. In contrast, LAD ligation IGF1R-KD mice presented significantly reduced EF 21dpi compared to the other 3 groups. Histological analysis revealed significant fibrosis in the IGF1R-KD LAD hearts compared to the other 3 groups. Conclusions: Whereas IGF1R-KD or control rAAV9 does not alter physiological cardiac development, KD of IGF1R markedly impairs neonatal cardiac regeneration in neonatal mice after MI suggesting a crucial role in neonatal cardiac regeneration.
Type of Medium:
Online Resource
ISSN:
0009-7322
,
1524-4539
DOI:
10.1161/circ.142.suppl_3.15735
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2020
detail.hit.zdb_id:
1466401-X
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