VIP gene deletion in mice causes cardiomyopathy associated with upregulation of heart failure genes

• Published in: PloS one 2013-05, Vol.8 (5), p.e61449
• Main Authors: Szema, Anthony M, Hamidi, Sayyed A, Smith, S David, Benveniste, Helene
• Format: Article
• Language: English
• Subjects: Animals; Arteries; Biology; Body temperature; Cardiomyopathies - genetics; Cardiomyopathies - metabolism; Cardiomyopathies - physiopathology; Cardiomyopathy; Deoxyribonucleic acid; DNA; DNA microarrays; Electrocardiography; Enlargement; Female; Gene Deletion; Genes; Genetic aspects; Genomes; Genomics; Heart diseases; Heart failure; Heart Failure - genetics; Heart Failure - metabolism; Heart Failure - physiopathology; Heart rate; Homeostasis; House mouse; Hypertension; Intestine; Kinases; Laboratories; Lungs; Magnetic resonance; Magnetic resonance imaging; Male; Medicine; Mice; Mice, Inbred C57BL; Mice, Knockout; MRI (magnetic resonance imaging); Muscles; Mutation; Myocardial diseases; NMR; Nuclear magnetic resonance; Oligonucleotide Array Sequence Analysis; Phenotype; Proteins; Pulmonary arteries; Pulmonary artery; Pulmonary hypertension; RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEAR CHEMISTRY; Rodents; Smooth muscle; Stroke Volume - genetics; Transcriptome; Up-Regulation; Vasoactive agents; Vasoactive intestinal peptide; Vasoactive Intestinal Peptide - deficiency; Vasoactive Intestinal Peptide - genetics; Vasodilator agents; Ventricle; VIP Gene Deletion in Mice Causes; Wall thickness; WT (wild type) mice
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0061449

Vasoactive Intestinal Peptide (VIP), a pulmonary vasodilator and inhibitor of vascular smooth muscle proliferation, is absent in pulmonary arteries of patients with idiopathic pulmonary arterial hypertension (PAH). We previously determined that targeted deletion of the VIP gene in mice leads to PAH with pulmonary vascular remodeling and right ventricular (RV) dilatation. Whether the left ventricle is also affected by VIP gene deletion is unknown. In the current study, we examined if VIP knockout mice (VIP(-/-)) develop both right (RV) and left ventricular (LV) cardiomyopathy, manifested by LV dilatation and systolic dysfunction, as well as overexpression of genes conducive to heart failure. We examined VIP(-/-)and wild type (WT) mice using Magnetic Resonance Imaging (MRI) for evidence of cardiomyopathy associated with biventricular dilation and wall thickness changes. Lung tissue from VIP(-/-) and WT mice was subjected to whole-genome gene microarray analysis. Lungs from VIP(-/-) mice showed overexpression of cardiomyopathy genes: Myh1 was upregulated 224 times over WT, and Mylpf was increased 72 fold. Tnnt3 was increased 105 times and tnnc2 181 fold. Hearts were dilated in VIP(-/-) mice, with thinning of LV wall and increase in RV and LV chamber size, though RV enlargement varied. Weights of VIP(-/-) mice were consistently lower. Critically-important heart failure-related genes are upregulated in VIP(-/-) mice associated with the spontaneous cardiomyopathy phenotype, involving both left and right ventricles, suggesting that loss of the VIP gene orchestrates a panoply of pathogenic genes which are detrimental to both left and right cardiac homeostasis.