Gene array analysis of a rat model of pulmonary arteriovenous malformations after superior cavopulmonary anastomosis

Tipps, Russell S.; Mumtaz, Muhammed; Leahy, Patrick; Duncan, Brian W.

doi:10.1016/j.jtcvs.2008.02.011

« Previous Next »The Journal of Thoracic and Cardiovascular Surgery
Volume 136, Issue 2 , Pages 283-289, August 2008

Gene array analysis of a rat model of pulmonary arteriovenous malformations after superior cavopulmonary anastomosis

Russell S. Tipps, BSc(Hons)
- Department of Pediatric and Congenital Heart Surgery, Children's Hospital, Cleveland Clinic, Cleveland, Ohio
Muhammed Mumtaz, MD
- Department of Pediatric and Congenital Heart Surgery, Children's Hospital, Cleveland Clinic, Cleveland, Ohio
Patrick Leahy, PhD
- Comprehensive Cancer Center, Case Western Reserve University School of Medicine and University Hospital, Cleveland, Ohio
Brian W. Duncan, MD
- Department of Pediatric and Congenital Heart Surgery, Children's Hospital, Cleveland Clinic, Cleveland, Ohio
- Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
- Address for reprints: Brian W. Duncan, MD, Pediatric and Congenital Heart Surgery/M41, Cleveland Clinic, 9500 Euclid Ave, Cleveland, Ohio 44195.

Received 22 March 2007; received in revised form 21 November 2007; accepted 12 February 2008.

Objective

Pulmonary arteriovenous malformations commonly develop in children who have undergone a cavopulmonary anastomosis as part of the palliative sequence for single-ventricle physiology.

Methods

We developed a rat model of cavopulmonary anastomosis that results in pulmonary arteriovenous malformations that are angiographically and histologically similar to the human condition. We used this model to analyze the gene expression profile associated with pulmonary arteriovenous malformations developing after cavopulmonary anastomosis.

Results

Six Sprague–Dawley rats underwent right superior cavopulmonary anastomosis, allowing the left lung to serve as a control. Total RNA was isolated from each lung at death 8 months postoperatively and compared by using the Affymetrix Rat Microarray RAE230 2.0 GeneChip (Affymetrix, Santa Clara, Calif). One hundred thirty-seven genes demonstrated altered expression in the lungs after cavopulmonary anastomosis compared with that seen in the control lungs: 55 (40%) genes demonstrated increased expression, and 82 (60%) genes demonstrated decreased expression. Modulation of genes associated with angiogenesis and vascular remodeling was found, including angiopoietin-2, placental growth factor, several matrix metalloproteases, and several collagen subtypes. Genes with vasoactive properties, including endothelin 1 and endothelin receptor type B, demonstrated altered gene expression. Several members of the transforming growth factor β superfamily signaling pathway also demonstrated altered expression.

Conclusions

These changes in gene expression might have causative implications for pulmonary arteriovenous malformations that develop after cavopulmonary anastomosis.

Abbreviations and Acronyms: Ang, angiopoietin, CPA, cavopulmonary anastomosis, ECM, extracellular matrix, ET, endothelin, MMP, matrix metalloproteinase, NPY, neuropeptide Y, PAVM, pulmonary arteriovenous malformation, RT-PCR, real-time polymerase chain reaction, TGF, transforming growth factor, TPA, tissue plasminogen activator