Changes and Distributions of Peptides Derived From Proadrenomedullin in Left-to-Right Shunt Pulmonary Hypertension of Rats

Abstract

Pulmonary hypertension (PHT) is a common complication of congenital heart disease and the pulmonary vascular structural remodeling because of the high pulmonary blood flow is considered to be the key pathologic process. In the present study the change and distribution of peptides derived from proadrenomedullin in a rat model of PHT caused by a left-to-right shunt were measured to elucidate the mechanism. Twelve weeks after a cervical shunt was established by a cuff technique in an experimental group of rats, the systolic pulmonary artery pressure (sPAP) was measured by catheterization. Morphologic assessment included the measurement of the weight ratio of the right ventricle (RV) to the left ventricle plus septum (LV+SP) and the mean percentage of media wall thickness (MT%) in moderate-sized pulmonary arteries. The distribution of adrenomedullin (ADM), adrenotensin (ADT) and proadrenomedullin N-terminal 20 peptide (PAMP) were measured by immunohistochemical staining. The mRNA expressions of ADM, ADT, PAMP and proADM45-92 were investigated by reverse transcription polymerase chain reaction. The sPAP and the ratios of RV/(LV+SP) and MT% were significantly increased in the experimental rats (p<0.01, and p<0.05). Positive signals (brown granules) of ADM, ADT and PAMP were mainly located in the smooth muscle cells, but the brown granules of PAMP were also located in the tunica adventitia. The levels of ADM and PAMP were significantly increased, while that of ADT was markedly decreased in the Experimental group compared with the Control group (p<0.05 and p<0.01 respectively). The mRNA expression levels of ADM and preADM45-92 were significantly increased in the experimental rats (p<0.01); however, the expression of ADT mRNA was statistically deceased in the Experimental group compared with the Control group (p<0.01). The mRNA expression of PAMP showed no statistical difference between the 2 groups of rats (p>0.05). The change and distribution of peptides derived from proadrenomedullin in PHT caused by a left-to-right shunt in rats is powerful evidence for intramolecular regulation.