Pulmonary hypertension (PH) develops as a result of the remodeling the pulmonary vasculature and is characterized by abnormal expansion of endothelial cells, medial hypertrophy, and adventitial thickening of pulmonary arteries, leading to obliteration of the arterial lumen, progressive right ventricular hypertrophy and eventually cardiac failure and death. Although any form of PH can contribute to the increased morbidity and mortality, pulmonary arterial hypertension (group 1) is particularly severe and progressive form with dismal prognosis. In the study of PAH pathobiology experimental animal models played a great role. The rat model of PH which is induced with the single subcutaneous/intraperitoneal injection of monocrotaline (MCT) has become popular in the general practice due to its high reproducibility, technical simplicity and low cost.
The article presents modern approaches to the understanding of the mechanisms involved into the development of monocrotaline induced pulmonary hypertension. MCT is naturally occurring pyrrolizidine alkaloid found in plant genus Crotalaria. Upon administration it undergoes biotransformation to reactive pyrrole (dehydromonocrotaline, DMCT) which exerts toxic effects on pulmonary circulation and liver. Progressive endothelial injury is speculated to trigger maladaptive remodeling of the pulmonary circulation with the abnormalities in nitric oxide signaling being shown to occur before the onset of PAH. Abnormal expression of vesicular transport proteins as well as bone morphogenetic protein type II receptor and endothelial nitric oxide synthase was noted during PAH development. Disruption of caveolae with a progressive loss of cav-1, which is involved in regulation of the inflammatory response, cell proliferation and apoptosis and inhibits number of mitogens implicated in PAH was suggested to be closely related to the MCT toxicity. Imbalance between apoptosis of endothelial cells and proliferation of pulmonary artery smooth muscle cells is a typical finding in MCT model of PH, which is currently attributed to the cav-1 associated activation of ERK1/2 signaling pathway with down-regulation of the bone morphogenetic protein signaling.
The inflammatory response in MCT model is caused not only by abnormalities in the cav-1 expression but also to activation of the systemic and pulmonary inflammatory response. Accumulation of the bone marrow derived macrophages and dendritic cells were detected in perivascular lesions both in PAH patients and MCT animals suggesting the pivotal role of the monocyte/macrophage activation for the pulmonary vascular remodeling. Altered inflammatory fibroblast phenotype is attributed to the epigenetic alteration, namely, increased catalytic activity and protein expression of class I histone acetyltransferases and histone deacetylases (HDACs). In turn, HDAC activity is significantly influenced by the pro-antioxidant balance in cells, pointing to the important role of oxidant status and oxidative stress in the development of monocrotaline induced PH. These assumptions were further corroborated by the findings that NLRP3 inflammasome is markedly up-regulated in MCT rats. Another important mechanism of action of MCT is formation of proteins and DNA adducts inducing cell cycle arrest and cell death.
MCT model of PH largely capture many of the cardinal features of the human disease such as endothelial cell damage, medial hypertrophy of the small pulmonary arteries, vascular inflammation, right ventricular hypertrophy. The pathogenetic similarities between monocrotaline-induced and human idiopathic pulmonary hypertension are discussed.
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