title: Long Non-Coding RNA Malat-1 Is Dispensable during Pressure Overload-Induced Cardiac Remodeling and Failure in Mice.
abstract: BACKGROUND
  Long non-coding RNAs (lncRNAs) are a class of RNA molecules with diverse regulatory functions during embryonic development, normal life, and disease in higher organisms. However, research on the role of lncRNAs in cardiovascular diseases and in particular heart failure is still in its infancy. The exceptionally well conserved nuclear lncRNA Metastasis associated in lung adenocarcinoma transcript 1 (Malat-1) is a regulator of mRNA splicing and highly expressed in the heart. Malat-1 modulates hypoxia-induced vessel growth, activates ERK/MAPK signaling, and scavenges the anti-hypertrophic microRNA-133. We therefore hypothesized that Malat-1 may act as regulator of cardiac hypertrophy and failure during cardiac pressure overload induced by thoracic aortic constriction (TAC) in mice.
  
  
  RESULTS
  Absence of Malat-1 did not affect cardiac hypertrophy upon pressure overload: Heart weight to tibia length ratio significantly increased in WT mice (sham: 5.78±0.55, TAC 9.79±1.82 g/mm; p<0.001) but to a similar extend also in Malat-1 knockout (KO) mice (sham: 6.21±1.12, TAC 8.91±1.74 g/mm; p<0.01) with no significant difference between genotypes. As expected, TAC significantly reduced left ventricular fractional shortening in WT (sham: 38.81±6.53%, TAC: 23.14±11.99%; p<0.01) but to a comparable degree also in KO mice (sham: 37.01±4.19%, TAC: 25.98±9.75%; p<0.05). Histological hallmarks of myocardial remodeling, such as cardiomyocyte hypertrophy, increased interstitial fibrosis, reduced capillary density, and immune cell infiltration, did not differ significantly between WT and KO mice after TAC. In line, the absence of Malat-1 did not significantly affect angiotensin II-induced cardiac hypertrophy, dysfunction, and overall remodeling. Above that, pressure overload by TAC significantly induced mRNA levels of the hypertrophy marker genes Nppa, Nppb and Acta1, to a similar extend in both genotypes. Alternative splicing of Ndrg2 after TAC was apparent in WT (isoform ratio; sham: 2.97±0.26, TAC 1.57±0.40; p<0.0001) and KO mice (sham: 3.64±0.37; TAC: 2.24±0.76; p<0.0001) and interestingly differed between genotypes both at baseline and after pressure overload (p<0.05 each).
  
  
  CONCLUSIONS
  These findings confirm a role for the lncRNA Malat-1 in mRNA splicing. However, no critical role for Malat-1 was found in pressure overload-induced heart failure in mice, despite its reported role in vascularization, ERK/MAPK signaling, and regulation of miR-133.
authors.affiliation: Center for Heart Failure Research, Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.
authors.forename: Tim
authors.initials: T
authors.lastname: Peters
authors.affiliation: Center for Heart Failure Research, Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.
authors.forename: Steffie
authors.initials: S
authors.lastname: Hermans-Beijnsberger
authors.affiliation: Department of Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Abdelaziz
authors.initials: A
authors.lastname: Beqqali
authors.affiliation: Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.
authors.forename: Nicole
authors.initials: N
authors.lastname: Bitsch
authors.affiliation: RNA Biology Laboratory, RIKEN, Wako, Saitama, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Nakagawa
authors.affiliation: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL, United States of America.
authors.forename: Kannanganattu V
authors.initials: KV
authors.lastname: Prasanth
authors.affiliation: Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.
authors.forename: Leon J
authors.initials: LJ
authors.lastname: de Windt
authors.affiliation: Department of Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: van Oort
authors.affiliation: Center for Heart Failure Research, Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.|Netherlands Heart Institute (ICIN), Utrecht, The Netherlands.|Centre for Molecular and Vascular Biology (CMVB), Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Stephane
authors.initials: S
authors.lastname: Heymans
authors.affiliation: Center for Heart Failure Research, Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.
authors.forename: Blanche
authors.initials: B
authors.lastname: Schroen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000804:Angiotensin II / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D001013:Aorta, Thoracic; D006332:Cardiomegaly / Q000209:etiology / Q000235:genetics*; D003251:Constriction, Pathologic / Q000150:complications; D003433:Crosses, Genetic; D005326:Fetal Proteins / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D006333:Heart Failure / Q000209:etiology / Q000235:genetics*; D006579:Heterozygote; D008026:Ligation; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D011312:Pressure; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing / Q000235:genetics*; D062085:RNA, Long Noncoding / Q000235:genetics / Q000502:physiology*; D020257:Ventricular Remodeling / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D005326:Fetal Proteins; C557040:Malat1 long non-coding RNA, mouse; C485172:Ndr2 protein, mouse; D011506:Proteins; D062085:RNA, Long Noncoding; D000804:Angiotensin II