| BACKGROUD: Pulmonary hypertension is a serious illness, with multiple potential causes that may progressively worsen and eventually prove fatal, which was classified into two categories: primary pulmonary hypertension and secondary pulmonary hypertension. Pulmonary hypertension is characterized by progressive remodeling of the small pulmonary arteries, causing increased resistance to blood flow in the lung, which, in turn, can raise the pulmonary arterial pressure. As the resistance rises, the afterload on the right ventricle increases, which leads to right ventricle remodeling and ultimately failure. Available treatments for pulmonary hypertension are limited, and often associated with significant side effects. Other deseases are associated with right ventricle remodeling such as left ventricular pathology, Chagas' disease, and arrhythmogenic right ventricle cardiomyopathy. The pathophysiology of right ventricular remodeling is a complex process. Due to the structure and function between the two chambers are very different, the right ventricular remodeling may include unique elements not observed in the left ventricular remodeling. Therefore, further understanding of these issues is of pivotal importance. The available treatments for right ventricle remodeling are also quite limited. Therefore, it is necessary to seek for some materials for treatment of pulmonary hypertension and right ventricle remodeling.Huilixinkang (GCIP-27) is a Gαq protein carboxyl terminus imitation polypeptide, which was cloned and constructed in our laboratory previously, prevent the hypertrophyic responses in cultured rat cardiomyocyte by noradrenaline (NA) and angiotensin II (AngII) and inhibited the left ventricular hypertrophy induced by NA or AngII in rats and mice, and also inhibited the left ventricular remodeling in spontaneously hypertensive rats (SHR). Interestingly, GCIP-27 inhibiting left ventricular remodeling is almost not depended on the effect of decreasing blood pressure in SHR. In addition, GCIP-27 inhibited the remodeling of aorta in SHR and prevented the proliferation responses responses in cultured vascular smooth muscle cell (VSMCs) by AngII. The polyphenolic compound resveratrol (Res, trans-3, 4', 5-trihydroxystilbene), is a naturally occurring phytochemical, which has been found in many plants. Relatively high quantity of Res is found in grapes. Res possesses a wide range of biological and pharmacological properties such as anti-oxidant, anti-inflammatory, anti-proliferation properties and the cardio-protective effects. Res inhibits the cardiomyocyte hypertrophy induced by AngII or PE in rat neonatal myocyte cultures, and the cardiac fibroblast proliferation. Res shows the protective effect on pulmonary endothelial cell, and represses the proliferation responses of in cultured VSMCs. In addition, the glycoside of Res was reported to prevent the pulmonary hypertension in the acute and chronic hypoxia animal model.AIM: The study is designed to study the potential effects of GCIP-27 on pulmonary hypertension and right ventricle remodeling using monocrotaline (MCT)-treated rats, and primarily analyze the mechanism.METHODs: Male Sprague-Dawley rats were given a single injection of MCT (50 mg/kg, sc) and then received treatment with vehicle or GCIP-27 (30, 90μg/kg, ip bid) or Res (10 and 30 mg/kg, ig, bid) from 1~21 days or 14~21days, respectively. The general state was observed. At the end of treatments, all survival rats received echocardiography to observe the RV free wall thickness (RVFWT), pulmonary arterial acceleration time (PAAT) and tricuspid regurgitation. All survival rats also received right catheterization to observe pulmonary arterial systolic pressure (PASP), pulmonary artery diastolic pressure (PADP), mean pulmonary arterial pressure (MPAP) and right ventricular systolic pressure (RVSP). In addition, right ventricular hypertrophy index (RVHI), right ventricular mass index (RVMI), lung index (LI) were obtained by weighting. Lung and right ventricles tissue were embedded in paraffin and stained with haematoxylin–eosin (HE), then examined under an optical microscope. Furthermore, the right ventricles were subjected to untrastructural analysis by transmission electron microscopy (TEM). The expression ofα-smooth muscle actin (α-SMA), proliferating cell nuclear antigen (PCNA) orⅧfactor antigen in pulmonary arteries and the expression of Bcl-2 and Bax antigen in right ventricles were done through immunohistochemical technique. The TdT mediated nick dUTP end labeling (TUNEL) technique was used to observe the apoptosis of cardiomyocytes in right ventricles. In addition, we used chocardiography to observed dynamic changes for PAAT, RVFVT and tricuspid regurgitation in some animals on 0 day, 14 day and 21day, respectively, which include animals treatment with GCIP-27 or Res from 14~21days, control animals and MCT model animals.RESULTs1. MCT produced 33% mortality in model rats, while no mortality occurs in animal treatment with Res or GCIP-272. As compared with 0 d, MCT significantly decreased PAAT on 14day and 21day, respectively (P<0.01). As compared with MCT group, both Res and GCIP-27 improved the decreased PAAT on 21day (P<0.05, P<0.01). As compared with 14day, the decreased PAAT could be ameliorated on 21day (P<0.05) in animals treatment with GCIP-27 or Res from 14~21days.3. As compared with the control group, MCT increased RVSP, PASP, PADP, MPAP (P<0.01). Except for PADP, Res improved all the above changes (P<0.05, P<0.01). GCIP-27 could improve the increased RVSP, PASP induced by MCT (P<0.05, P<0.01), but only the treatment with high dose of GCIP-27 (90μg/kg) from 1~21 day improved the increased MPAP induced by MCT (P<0.05).4. As compared with the control group, MCT effectively increased LI, the pulmonary arterial medial thickness and the expression ofα-SMA antigen and PCNA antigen in pulmonary arterial smooth muscle cell (PASMCs). Both Res and GCIP-27 improved all these changes to some extent (P<0.05, P<0.01).5. As compared with the control group, MCT also effectively decreased the expression ofⅧfactor antigen in the PAs and the number of pulmonary capillary (P<0.01), however, Res improved these changes (P<0.05, P<0.01).6. As compared with 0 d, MCT increased RVFWT on 14day and 21day (P<0.01), respectively, and induced 75% tricuspid regurgitation on 21day. As compared with in MCT group, both Res and GCIP-27 could improve the increased RVFWT induced by MCT (P<0.05, P<0.01). No tricuspid regurgitation occured in animal treatment with Res or GCIP-27. As compared with 14day, the increased RVFWT could be ameliorated on 21day in animals treatment with GCIP-27 or Res from 14~21days (P<0.01).7. As compared with the control group, MCT increased the RVHI, RVMI (P<0.01). However, GCIP-27 and Res improved all these changes (P<0.05, P<0.01).8. In MCT-treated rats, the microstructure of right ventricles was as follows: the cardiomyocytes hypertrophy, interstitium fibrosis and myofibrilla lined up in disorder. However, both GCIP-27 and Res improved these morphological changes to some extent. 9. In MCT-treated rats, the ultrastructure of right ventricular cadiocytes was observed as the mitochondria swell and medullary sheath-like degeneration, the sarcoplasmic reticulum enlarged and the myofilaments dissolved and the Z lines broken. However, GCIP-27 and Res improved these morphological changes.10. As compared with the control group, MCT induced the apoptosis of cardiomyocytes and the over-expression of the Bax antigen and the low-expression of Bcl-2 antigen in the right ventricle tissues, respectively (P<0.01). However, both Res and GCIP-27 markedly attenuated the above changes (P<0.05, P<0.01).CONCLUSION1. Huilixinkang (GCIP-27) significantly inhibits right ventricle remodeling induced by MCT. The mechanism is associated with the anti-apoptosis effect in right ventricular cardiomyocytes and the effect of reducing pulmonary hypertension to some extent.2. GCIP-27 significantly attenuates the apoptosis of right ventricular cardiomyocytes in MCT-treated rats. The mechanism is relative to the overexpression of Bcl-2 antigen, low expression of Bax antigen, the protective effect of mitochondrium in right ventricular cardiomyocytes as well as the effect of reducing pulmonary hypertension to some extent.3. GCIP-27 inhibits the pulmonary hypertension to some extent, which is relative to the impressing effect on the proliferation of PASMCs and pulmonary artery remodeling.4. Res inhibits right ventricle remodeling induced by MCT. The mechanism is associated with the anti-apoptosis effect in right ventricular cardiomyocytes and the reducing pulmonary hypertension effect significantly.5. Res significantly attenuates the apoptosis of right ventricular cardiomyocytes in MCT-treated rats. The anti-apoptotic effects is relative to the overexpression of Bcl-2 antigen, low expression of Bax antigen, the protective effect of mitochondria in right ventricular cardiomyocytes as well as the significant effect of reducing pulmonary hypertension.6. Res significantly inhibits the pulmonary hypertension, which is relative to the impressing effect on the proliferation of PASMCs, pulmonary artery remodeling, and the increased number of pulmonary capillary in MCT- treated rats.
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