The monocrotaline model of pulmonary hypertension in perspective
ABSTRACT Severe forms of pulmonary arterial hypertension (PAH) are characterized by various degrees of remodeling of the pulmonary arterial vessels, which increases the pulmonary vascular resistance and right ventricular afterload, thus contributing to the development of right ventricle dysfunction and failure. Recent years have seen advances in the understanding of the pathobiology of PAH; however, many important questions remain unanswered. Elucidating the pathobiology of PAH continues to be critical to design new effective therapeutic strategies, and appropriate animal models of PAH are necessary to achieve the task. Although the monocrotaline rat model of PAH has contributed to a better understanding of vascular remodeling in pulmonary hypertension, we question the validity of this model as a preclinically relevant model of severe plexogenic PAH. Here we review pertinent publications that either have been forgotten or ignored, and we reexamine the monocrotaline model in the context of human forms of PAH.
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- "Since RV function is a critical prognostic determinant in PH , RV dysfunction has often been studied in animal models of PH, such as the monocrotaline rat model . Although these models have proven to be valuable, they have two important disadvantages: direct therapeutic effects on the RV cannot be distinguished from (afterload-reducing) effects on the pulmonary vasculature and the used 'hits' necessary to induce PH may affect the RV . The use of a pulmonary artery banding (PAB) to inflict chronic pressure load on the RV circumvents these limitations . "
ABSTRACT: Right ventricular failure (RVF) due to pressure load is a major cause of death in congenital heart diseases and pulmonary hypertension. The mechanisms of RVF are unknown. We used an experimental approach based upon clinical signs of RVF to delineate functional and biological processes associated with RVF. and Results Wistar rats were subjected to a pulmonary artery banding (PAB n=12) or sham surgery (CON, n=7). After 52±5days, 5/12 PAB rats developed clinical symptoms of RVF (inactivity, ruffled fur, dyspnea, ascites) necessitating termination (PAB+CF). We compared these to PAB rats with RVF without clinical symptoms (PAB-). PAB resulted in reduced cardiac output, RV stroke volume, TAPSE, and increased end diastolic pressure (all p<0.05 vs. CON) in all rats, but PAB+CF rats were significantly more affected than PAB-, despite similar pressure load (p=ns). Pressure-volume analysis showed enhanced contractility (end systolic elastance) in PAB- and PAB+CF, but diastolic function (end diastolic elastance, end diastolic pressure) deteriorated especially in PAB+CF. In PAB+CF capillary density was lower than in PAB-. Gene-array analysis revealed downregulation of both fatty acid oxidation and carbohydrate metabolism in PAB+CF. Chronic PAB led to different degrees of RVF, with half of the rats developing severe clinical symptoms of RVF, associated with progressive deterioration of diastolic function, hypoxia-prone myocardium, increased response to oxidative stress and suppressed myocardial metabolism. This model represents clinical RVF and allows for unraveling of mechanisms involved in the progression from RV adaptation to RV failure and the effect of intervention on these mechanisms. Copyright © 2014. Published by Elsevier Ltd.Journal of Molecular and Cellular Cardiology 12/2014; 79. DOI:10.1016/j.yjmcc.2014.11.024 · 5.22 Impact Factor
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ABSTRACT: Pulmonary hypertension (PH) is a disease of high lethality arising from numerous causes. For a significant subset of PH patients, autoimmune biomarkers or frank autoimmune disease are simultaneously present, but the extent to which lung inflammation contributes to PH is unknown. However, emerging experimental and clinical evidence suggests that immune dysregulation may lead to the propagation of vascular injury and PH. A recent preclinical study demonstrated that regulatory T cells are important mediators normally enlisted to control inflammation and that, if absent or dysfunctional, may predispose to the development of PH.Trends in cardiovascular medicine 08/2011; 21(6):166-71. DOI:10.1016/j.tcm.2012.05.004 · 2.07 Impact Factor
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ABSTRACT: Genetically modified mouse models have unparalleled power to determine the mechanisms behind different processes involved in the molecular and physiologic etiology of various classes of human pulmonary hypertension (PH). Processes known to be involved in PH for which there are extensive mouse models available include the following: (1) Regulation of vascular tone through secreted vasoactive factors; (2) regulation of vascular tone through potassium and calcium channels; (3) regulation of vascular remodeling through alteration in metabolic processes, either through alteration in substrate usage or through circulating factors; (4) spontaneous vascular remodeling either before or after development of elevated pulmonary pressures; and (5) models in which changes in tone and remodeling are primarily driven by inflammation. PH development in mice is of necessity faster and with different physiologic ramifications than found in human disease, and so mice make poor models of natural history of PH. However, transgenic mouse models are a perfect tool for studying the processes involved in pulmonary vascular function and disease, and can effectively be used to test interventions designed against particular molecular pathways and processes involved in disease.01/2012; 2(4):415-433. DOI:10.4103/2045-8932.105030