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Trimedazidine alleviates pulmonary artery banding-induced acute right heart dysfunction and activates PRAS40 in rats.

ABSTRACT: The molecular mechanism underlying acute right heart failure (RHF) is poorly understood. We used pulmonary artery banding (PAB) to induce acute RHF characterized by a rapid rise of right ventricular pressure, and then a decrease in right ventricular pressure along with a decrease in blood pressure right after banding. We found higher brain natriuretic peptide (BNP) and beta-myosin heavy chain (?MHC) levels and lower alpha-myosin heavy chain (?MHC) levels in RHF rats than sham-operated rats. Hemodynamic indexes in rats with acute RHF were slightly improved by trimedazidine TMZ, a key inhibitor of fatty acid (FA) oxidation. TMZ also reversed downregulation of peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC-1?) and peroxisome proliferator-activated receptor alpha (PPAR?) by PAB and up-regulates peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1?), peroxisome proliferator-activated receptor delta (PPAR?) and pyruvate dehydrogenase kinase isoform 4 (PDK4). In addition, TMZ reversed upregulation of phosphorylated Akt by PAB and increased phosphorylated proline-rich Akt-substrate 40 (PRAS40). Autophagy and apoptosis were not modified by PAB or TMZ. An acute RHF model was established in rats through 70% constriction of the pulmonary artery. TMZ treatment alleviated PAB-induced acute RHF by activating PRAS40 and upregulatingPGC-1?, PGC-1?, PPAR?, PPAR?, and PDK4.

SUBMITTER: Cao Y

PROVIDER: S-EPMC5696164 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Trimedazidine alleviates pulmonary artery banding-induced acute right heart dysfunction and activates PRAS40 in rats.

Cao Yunshan Y Song Jiyang J Shen Shutong S Fu Heling H Li Xiang X Xu Ying Y Wang Aqian A Li Xinli X Zhang Min M

Oncotarget 20170908 54

The molecular mechanism underlying acute right heart failure (RHF) is poorly understood. We used pulmonary artery banding (PAB) to induce acute RHF characterized by a rapid rise of right ventricular pressure, and then a decrease in right ventricular pressure along with a decrease in blood pressure right after banding. We found higher brain natriuretic peptide (BNP) and beta-myosin heavy chain (βMHC) levels and lower alpha-myosin heavy chain (αMHC) levels in RHF rats than sham-operated rats. Hemo ...[more]

PMID: 29190898

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Project description:Decompensated right ventricular failure (RVF) in pulmonary hypertension (PH) is fatal, with limited medical treatment options. Developing and testing novel therapeutics for PH requires a clinically relevant large animal model of increased pulmonary vascular resistance and RVF. This manuscript discusses the latest development of the previously published ovine PH-RVF model that utilizes left pulmonary artery (PA) ligation and main PA occlusion. This model of PH-RVF is a versatile platform to control not only the disease severity but also the RV's phenotypic response. Adult sheep (60-80 kg) underwent left PA (LPA) ligation, placement of main PA cuff, and insertion of RV pressure monitor. PA cuff and RV pressure monitor were connected to subcutaneous ports. Subjects underwent progressive PA banding twice per week for 9 weeks with sequential measures of RV pressure, PA cuff pressures, and mixed venous blood gas (SvO2). At the initiation and endpoint of this model, ventricular function and dimensions were assessed using echocardiography. In a representative group of 12 animal subjects, RV mean and systolic pressure increased from 28 ± 5 and 57 ± 7 mmHg at week 1, respectively, to 44 ± 7 and 93 ± 18 mmHg (mean ± standard deviation) by week 9. Echocardiography demonstrated characteristic findings of PH-RVF, notably RV dilation, increased wall thickness, and septal bowing. The longitudinal trend of SvO2 and PA cuff pressure demonstrates that the rate of PA banding can be titrated to elicit varying RV phenotypes. A faster PA banding strategy led to a precipitous decline in SvO2 < 65%, indicating RV decompensation, whereas a slower, more paced strategy led to the maintenance of physiologic SvO2 at 70%-80%. One animal that experienced the accelerated strategy developed several liters of pleural effusion and ascites by week 9. This chronic PH-RVF model provides a valuable tool for studying molecular mechanisms, developing diagnostic biomarkers, and enabling therapeutic innovation to manage RV adaptation and maladaptation from PH.

Dataset Information

Trimedazidine alleviates pulmonary artery banding-induced acute right heart dysfunction and activates PRAS40 in rats.

Publications

Trimedazidine alleviates pulmonary artery banding-induced acute right heart dysfunction and activates PRAS40 in rats.

Similar Datasets

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