Supplementary MaterialsSupplementary Data

Supplementary MaterialsSupplementary Data. cardiac output, and exercise capacity at 4 weeks post-SU. Moreover, microarray analysis revealed that over 300 genes were uniquely regulated in the RV in the severe PAH model in the Fischer compared with SD rats, mainly related to angiogenesis and vascular homoeostasis, fatty acid metabolism, and innate immunity. A focused polymerase chain reaction array confirmed down-regulation of angiogenic genes in the Fischer compared with SD RV. Furthermore, Fischer rats exhibited significantly lower RV capillary density compared with SD rats in response to SUHx. Conclusion Fischer rats are prone to develop RV failure in response to increased afterload. Moreover, the high mortality in the SUHx model of Rabbit polyclonal to ALDH1L2 severe PAH was caused by a failure of RV adaptation associated with lack of adequate microvascular angiogenesis, together with metabolic and immunological responses in the hypertrophied RV. and ?andand and Supplementary material online, and and Supplementary material online, (endothelin receptor Type B), (prostacyclin synthase), (Atrial Natriuretic Peptide-Converting Enzyme), (endothelin-1), (Chemokine (C-C Motif) Receptor 2), and (Atrial natriuretic peptide, ANP). Down-regulated genes in Fischer rats with severe PH included those related to natural killer (NK)-cells (expression and up-regulation of expression in Fischer SUHx was attributable Cyclazodone almost entirely to the low Cyclazodone basal expression in the control Fischer rats; however, protein levels of and were comparable in Fischer and SD RV both at baseline and in response to SUHx (Supplementary material online, and Supplementary material online, and and and Supplementary material online, angiogenic activity,30 suggesting that differences in the neovascularization of the hypertrophied myocardium may be critical for adequate RV adaptation. In our study, we also observed a marked reduction in RV capillary density in the severe PAH model, which was more marked in Fischer compared with SD rats. The decrease in myocardial capillaries seen on thin sections was confirmed by FMA which provides 3-dimensional imaging of the functional microvascular architecture in solid (40 micron) sections of the RV therefore yielding a Cyclazodone quantitative assessment of RV capillaries much like rigorous methods, such as unbiased stereology.31,32 Reduced RV vascularity was associated with a decrease in expression of angiogenic genes in the RV of Fischer rats compared with SD rats, again consistent with the emerging concept that microvascular angiogenesis is critical for adaptive RV remodelling in response to marked increases in afterload associated with severe PH. Indeed, our group has recently exhibited that cardiotrophin-1, an interleukin cytokine superfamily member which promotes physiological myocardial remodelling and angiogenesis, improved capillary density, reversed dilation, and restored contractile function of the RV in the Fischer rat SUHx model.33 4.1 Limitations This study has several limitations which are important to note. Although, we provide evidence to support RV dysfunction, including RV dilatation and decreased RVEF and CO using both MRI and echocardiography, we did not assess pressureCvolume loops, which is the gold-standard for examining RV-pulmonary arterial coupling and contractility. Also, only male animals were studied and the relative ability of the RV female SD and Fischer rats to adapt to pressure overload needs to be assessed in future studies. 5. Conclusion In conclusion, we have exhibited that Fischer rats develop maladaptive RV remodelling in the SUHx model of severe PAH, which may lead to early mortality. This was associated with impairment in the RV angiogenesis, NK cells and dysregulated expression in a number of gene families associated with vascular homoeostasis, Cyclazodone inflammation, and cardiac metabolism. Our findings suggest that the Fischer rat strain may be uniquely suited for the study of RV decompensation in response to severe PH, and provide a RV failure-prone model for the further exploration of molecular mechanisms underlying maladaptive remodelling, as well as for the study of novel RV-targeted therapies. Supplementary Material Supplementary.