Abstract
RationaleVasoactive 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.MethodsWe 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.ResultsLungs 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.ConclusionsCritically-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.
Highlights
Idiopathic pulmonary arterial hypertension (PAH) is a relatively uncommon [1] but highly fatal disease [2] characterized by progressive PAH and increased thickening of smaller pulmonary arteries and arterioles, culminating in right ventricular (RV) failure [3]
We examined VIP2/2and wild type (WT) mice using Magnetic Resonance Imaging (MRI) for evidence of cardiomyopathy associated with biventricular dilation and wall thickness changes
Hearts were dilated in VIP2/2 mice, with thinning of left ventricular (LV) wall and increase in RV and LV chamber size, though RV enlargement varied
Summary
Idiopathic (primary) pulmonary arterial hypertension (PAH) is a relatively uncommon [1] but highly fatal disease [2] characterized by progressive PAH and increased thickening of smaller pulmonary arteries and arterioles, culminating in right ventricular (RV) failure [3]. We reported that the medial wall of pulmonary arteries (45 to 50 mm diameter), was significantly thicker and the lumen was significantly narrower in VIP2/2 mice compared to control WT mice [6]. The most striking abnormality observed in VIP2/ 2 was that numerous pulmonary vessels were so severely narrowed they appeared almost totally occluded. Clusters of inflammatory cells, predominantly mononuclear infiltrates, were observed around smaller pulmonary vessels and airways [6]. Using invasive post-mortem techniques, we further documented that the (RV septum/LV+septum) weight ratio, in male VIP2/2 mice was significantly higher than in male control WT mice – suggestive of relative RV hypertrophy
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