A unique microRNA profile in end-stage heart failure indicates alterations in specific cardiovascular signaling networks.
It is well established that the gene expression patterns are substantially altered in cardiac hypertrophy and heart failure, however, less is known about the reasons behind such global differences. MicroRNAs (miRNAs) are short non-coding RNAs that can target multiple molecules to regulate wide array of proteins in diverse pathways. The goal of the study was to profile alterations in miRNA expression using end-stage human heart failure samples with an aim to build signaling network pathways using predicted targets for the altered miRNA and to determine nodal molecules regulating individual networks. Profiling of miRNAs using custom designed microarray and validation with an independent set of samples identified eight miRNAs that are altered in human heart failure including one novel miRNA yet to be implicated in cardiac pathology. To gain an unbiased perspective on global regulation by top eight altered miRNAs, functional relationship of predicted targets for these eight miRNAs were examined by network analysis. Ingenuity Pathways Analysis network algorithm was used to build global signaling networks based on the targets of altered miRNAs which allowed us to identify participating networks and nodal molecules that could contribute to cardiac pathophysiology. Majority of the nodal molecules identified in our analysis are targets of altered miRNAs and known regulators of cardiovascular signaling. Cardio-genomics heart failure gene expression public data base was used to analyze trends in expression pattern for target nodal molecules and indeed changes in expression of nodal molecules inversely correlated to miRNA alterations. We have used NF kappa B network as an example to show that targeting other molecules in the network could alter the nodal NF kappa B despite not being a miRNA target suggesting an integrated network response. Thus, using network analysis we show that altering key functional target proteins may regulate expression of the myriad signaling pathways underlying the cardiac pathology.
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
Sathyamangla V
SV
Naga Prasad
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
Manveen K
MK
Gupta
Department of Computer Sciences, University of Akron, Akron, Ohio, United States of America.
Zhong-Hui
ZH
Duan
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
Venkata Suresh K
VS
Surampudi
Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, United States of America.
Chang-Gong
CG
Liu
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
Ashwin
A
Kotwal
Department of Cardiovascular Medicine, Heart and Vascular Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
Christine S
CS
Moravec
Department of Cardiovascular Medicine, Heart and Vascular Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
Randall C
RC
Starling
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
Dianne M
DM
Perez
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
Subha
S
Sen
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
Qingyu
Q
Wu
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
Edward F
EF
Plow
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
Sadashiva
S
Karnik
D000465:Algorithms; D000818:Animals; D002319:Cardiovascular System / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D053263:Gene Regulatory Networks / Q000235:genetics*; D023281:Genomics / Q000379:methods; D006333:Heart Failure / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D015398:Signal Transduction / Q000235:genetics*
D035683:MicroRNAs