Author + information
- Wolfgang Pollera,b,
- Martina Gasta,b,
- Bernhard Raucha,b,
- Shinichi Nakagawaa,b,
- Kannanganattu Prasantha,b,
- Andrea Strouxa,b,
- Jan Haasa,b,
- Benjamin Medera,b,
- Carsten Skurka,b,
- Ursula Rauch-Kröhnerta,b and
- Ulf Landmessera,b
Background: Inflammation is a key driver of atherosclerosis and myocardial infarction (MI). We previously found that long noncoding RNA (lncRNA) MALAT1 has immunoregulatory functions and adversely affects the outcome of Coxsackievirus B3 myocarditis (Gast et al. J Mol Cell Biol 2016;8:178-81). Here we report on immune system dysregulation and accelerated atherosclerosis in MALAT1-deficient ApoE -/- mice.
Methods: Analysis of immune system regulation (using microarray- and qPCR-based expression profiling, histology, immunohistochemistry) and atherosclerosis development in MALAT1-/+ ApoE-/- heterozygous/homozygous knockout mice.
Results: For the current project we attempted to breed double knockout MALAT1-/- ApoE-/- mice, but apparently full double knockout was associated with intrauterine lethality. MALAT1-/+ ApoE-/- mice, in contrast, could be raised without apparent phenotype. At transcriptome level, however, MALAT1-/+ ApoE-/- splenocytes displayed a major anomaly with significant (p<0.001) downregulation of FAS to 50% of the level in MALAT1+/+ ApoE-/- mice. Remarkably, there was no such downregulation in MALAT1+/+ ApoE-/- vs. wildtype mice, thus downregulation is unequivocally caused by the heterozygous MALAT1-/+ defect. Similarly, aortae of MALAT1-/+ ApoE-/- mice had significant downregulation of the RIG-like receptor IFIH1 (MDA-5, RLR-2) (p<0.001) and IFITM1 (p<0.05) vs. MALAT1+/+ ApoE-/- mice, but no such downregulation in MALAT1+/+ ApoE-/- vs. wildtype. Conventional histological and immunohistochemical studies revealed significantly (p<0.01) aggravated plaque formation in the aortic roots of MALAT1-/+ ApoE-/- vs. MALAT1+/+ ApoE-/- mice.
Conclusions: Subtle anomalies of immune system regulation associated with partial deficiency of lncRNA MALAT1 may aggravate atheropathogenesis when occurring on predisposing genetic background such as Apo E-/-. Unusual is the strength of the effect of only heterozygous MALAT1-/+ deficiency upon important immunregulatory proteins (FAS, IFIH1). The data suggest that normal MALAT1 levels may be required to “buffer” the effects of potentially pathogenic immunological stress in genetically predisposed individuals
Moderated Poster Contributions
Vascular Medicine Moderated Poster Theater, Poster Hall, Hall C
Sunday, March 19, 2017, 12:45 p.m.-12:55 p.m.
Session Title: Mechanisms of Vascular Inflammation in Atherogenesis
Abstract Category: 38. Vascular Medicine: Basic
Presentation Number: 1320M-05
- 2017 American College of Cardiology Foundation