Dataset Information

A Feline HFpEF Model with Pulmonary Hypertension and Compromised Pulmonary Function.

ABSTRACT: Heart Failure with preserved Ejection Fraction (HFpEF) represents a major public health problem. The causative mechanisms are multifactorial and there are no effective treatments for HFpEF, partially attributable to the lack of well-established HFpEF animal models. We established a feline HFpEF model induced by slow-progressive pressure overload. Male domestic short hair cats (n?=?20), underwent either sham procedures (n?=?8) or aortic constriction (n?=?12) with a customized pre-shaped band. Pulmonary function, gas exchange, and invasive hemodynamics were measured at 4-months post-banding. In banded cats, echocardiography at 4-months revealed concentric left ventricular (LV) hypertrophy, left atrial (LA) enlargement and dysfunction, and LV diastolic dysfunction with preserved systolic function, which subsequently led to elevated LV end-diastolic pressures and pulmonary hypertension. Furthermore, LV diastolic dysfunction was associated with increased LV fibrosis, cardiomyocyte hypertrophy, elevated NT-proBNP plasma levels, fluid and protein loss in pulmonary interstitium, impaired lung expansion, and alveolar-capillary membrane thickening. We report for the first time in HFpEF perivascular fluid cuff formation around extra-alveolar vessels with decreased respiratory compliance. Ultimately, these cardiopulmonary abnormalities resulted in impaired oxygenation. Our findings support the idea that this model can be used for testing novel therapeutic strategies to treat the ever growing HFpEF population.

SUBMITTER: Wallner M

PROVIDER: S-EPMC5707379 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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A Feline HFpEF Model with Pulmonary Hypertension and Compromised Pulmonary Function.

Wallner Markus M Eaton Deborah M DM Berretta Remus M RM Borghetti Giulia G Wu Jichuan J Baker Sandy T ST Feldsott Eric A EA Sharp Thomas E TE Mohsin Sadia S Oyama Mark A MA von Lewinski Dirk D Post Heiner H Wolfson Marla R MR Houser Steven R SR

Scientific reports 20171129 1

Heart Failure with preserved Ejection Fraction (HFpEF) represents a major public health problem. The causative mechanisms are multifactorial and there are no effective treatments for HFpEF, partially attributable to the lack of well-established HFpEF animal models. We established a feline HFpEF model induced by slow-progressive pressure overload. Male domestic short hair cats (n = 20), underwent either sham procedures (n = 8) or aortic constriction (n = 12) with a customized pre-shaped band. Pul ...[more]

PMID: 29185443

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Project description:Pulmonary hypertension (PH) and cancer pathophysiology share common signal transduction pathways leading to abnormal endothelial and smooth muscle cell interactions and angioproliferative vasculopathy. Sorafenib (Sor) a drug in clinical trials for cancer treatment, is an inhibitor of multiple kinases important in angiogenesis (Raf-1 kinase, VEGFR-2, VEGFR-3, PDGFR-ï¢)ï©. In this study, we assessed the efficacy of Sor as a potential therapy for PH, and hypothesized that Sor prevents the development of both a conventional and an augmented rodent model of PH. We performed studies in Dahl Salt-Sensitive rats (SS) exposed to hypoxia alone and in combination with the VEGFR-2 inhibitor, SU5416, known to induce a well-characterized augmented PH phenotype. Rats were, thus, divided into 5 groups: normoxia/vehicle (Norm), hypoxia/vehicle (H), hypoxia/ SU5416 (H-SU), hypoxia/Sorafenib (H-Sor) and hypoxia/ SU5416/ Sorafenib (H-SU-Sor). Except for the Norm group, all rats were maintained in a hypoxia chamber with a FiO2 of 10%. Rats received a single injection of SU5416 on Day 1 (20 mg/kg) and Sor solution was administered daily by gavage (2.5mg/kg). After 3.5 weeks, all rats were assessed by open chest catheterizations for pulmonary vascular and right ventricular pressures. Lung and heart tissue were harvested for histological and microarray analyses. Our results showed H-SU rats developed severe PH with changes in hemodynamic and histologic parameters when compared to Norm controls while rats exposed to H alone only displayed mildly elevated pressures compared with Norm. There was no significant change in pressures in the H-Sor or H-SU-Sor compared to Norm. Histopathology demonstrated a dramatic prevention of the PH phenotype in the H-SU-Sor rats with no significant remodeling compared with H-SU rats. Expression profiling data from H (n=4) and H-SU (n=3) rat lungs were compared to Norm (n=4) using normalization in R and SAM (Î´>.639,) (minimum fold change >1.4). With false discovery rates (FDR) of 6.5% in hypoxia and 1.6% in H-SU, 1019 and 465 genes, respectively, were differentially-regulated compared to Norm. In addition, 38 genes were differentially expressed between H-SU and H-SU-Sor (n=4, FDR 6.7%) revealing a molecular signature with potentially novel target genes of Sor. Five differentially expressed genes (Tgfï¢3, C1qg, Nexn, Frzb, and Plaur) were examined by real-time RT-PCR and three were further validated by immunohistochemistry confirming the regulation on protein level. Based on the known pathways of hypoxic-induced PH and Sor, we further utilized immunohistochemistry to show the up-regulation of mediators of the MAPK cascade in the H and H-SU models of PH with subsequent, down-regulation by Sor. We therefore present Sor as a novel treatment for the development of severe PH and theorize that the MAPK cascade is a canonical pathway involved both in the development of PH and in the attenuation by Sor. Experiment Overall Design: Rats were divided into 5 groups of which 4 groups were analyzed by microarrays: normoxia/vehicle (n=4), hypoxia/vehicle (n=4), hypoxia/ SU5416 (n=3), and hypoxia/ SU5416/ Sorafenib (n=4). RNA was harvested from lung tissue at 3.5 weeks.Expression profiling data from H and H-SU rat lungs were compared to Norm using normalization in R and SAM (Î´>.639,) (minimum fold change >1.4). With false discovery rates (FDR) of 6.5% in hypoxia and 1.6% in H-SU, 1019 and 465 genes, respectively, were differentially-regulated compared to Norm. In addition, 38 genes were differentially expressed between H-SU and H-SU-Sor (FDR 6.7%) revealing a molecular signature with potentially novel target genes of Sor.

Dataset Information

A Feline HFpEF Model with Pulmonary Hypertension and Compromised Pulmonary Function.

Publications

A Feline HFpEF Model with Pulmonary Hypertension and Compromised Pulmonary Function.

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