Global analysis of transcription remodeling in heart and brain in a rat model of heart failure‐induced by myocardial infarction

Myocardial infarction (MI)‐induced heart failure (HF) is a devastating disease with high incidences that threats millions of patients in the U.S. MI‐induced HF causes irreversible injury to the heart as well as many other organs affected by insufficient blood supply. The impaired cardiac function in HF also evokes neural and humoral compensatory mechanisms to maintain blood pressure and the performance of heart. Permanent damages in these organs and subsequent compensatory responses caused by MI may result in transcriptional modification or epigenetic changes in chromatins of relevant regions in the development of HF. However, the alternations of gene expression affected by MI in HF is not completely understood. The present study sought to determine the transcription landscape remodeling and adaptive epigenetic alternation in MI‐induced HF rat. To gain insights into global transcriptional changes, we used an unbiased whole‐genome RNA sequencing approach to interrogate the transcriptional differences in heart and brain in MI‐induced HF vs. sham rats. Male Sprague‐Dawley rats underwent left anterior descending (LAD) coronary artery ligation to induce HF or sham operation (Sham). Myocardial infarction in HF was confirmed by echocardiography. Heart and brain were collected two weeks after LAD ligation. The total RNA was extracted from myocardial tissues adjacent to the infracted zone and hypothalamic paraventricular nucleus (PVN), an important cardiovascular/autonomic brain. Principle component analysis (PCA) shows that the heart and PVN samples of HF rats (n=4) were well separated from their counterparts of Sham rats (n=4), respectively. We detected 865 upregulated and 245 downregulated differentially expressed genes (DEGs) in the heart ( p value cut‐off is set to <0.01, and threshold of fold change cut‐off is set to >2 for upregulation or <1/2 for downregulation), while 35 upregulated and 39 downregulated DEGs were identified in PVN in HF animals ( p value cut‐off is set to <0.05, and threshold of fold change cut‐off is set to >1.2 for upregulation or <0.8 for downregulation). Moreover, enrichment analysis using gene ontology database KEGG (Kyoto Encyclopedia of Genes and Genomes) has identified 25 pathways in the heart. Each pathway contains 9‐34 DEGs. Meanwhile, MI‐induced DEGs in PVN are categorized into several pathways that are associated with angiotensin and angiogenesis ( e.g. aplnr ), MAP kinase signaling cascades ( e.g. map3k6 ), hypoxia responses ( e.g. Hif3a ), neural activity and inflammation/immune activation, et. al. Further study will determine the functional significance of these DEGs in HF. Collectively, these data reveal a regulatory feedback loop along the heart‐brain axis and suggest a previously unrecognized transcriptional remodeling mechanism in the brain that may contribute to the neurohormonal and autonomic regulation in HF.