| Background: Hydrogen Sulfide (H2S) is regarded as the third endogenous signaling gasotransmitter, besides nitric oxide (NO) and carbon monoxide (CO). It plays important roles under some physiological and pathological conditions, especially in cardiovascular system. It is well known that cardiac hypertrophy is the common pathological change in cardiovascular system, and it is also an independent risk factor of worsening heart function and sudden cardiac death. So, preventing the development of cardiac hypertrophy may help to decrease the morbidity and mortality of cardiovascular disease. It is acknowledged that renin-angiotensin system (RAS) plays important roles in the occurrence and development of cardiac hypertrophy. Therefore, we made the model of cardiac hypertrophy induced by abdominal aortic ligation, to observe the effects of hydrogen sulfide administration on cardiac hypertrophy and fibrosis, the levels of angiotensin-Ⅱ(Ang-Ⅱ) in cardiac and plasma, and the concentrations of connexin 43 (Cx43) in myocardial tissue, and to explore the related mechanisms.Methods: Adult male Sprague–Dawley rats (8 weeks, 170–190 g) were divided randomly into 3 groups: 1) untreated control (normal, n=10); 2)Sham operated group (sham, n=10); 3)abdominal aortic coarctation (AAC, n=80). The surgical procedure was executed according to established process, and those survival AAC rats after one week were divided randomly into: 1) abdominal aortic coarctation only (AAC, n=14); 2) surgery plus enalapril given by direct gastric gavage (AAC+enalapril, 5mg/kg/d, n=14); 3) surgery plus hydrogen sulfide administration intraperitoneally (AAC+H2S, 14umol/kg/d, n=14). The Sham operated animals serving as controls were subjected to the same surgical procedure except that their aortas were not constricted. The drugs were given every morning one week after surgery, and the rats were sacrificed 5 weeks after surgery. The hearts were removed and the blood in abdominal artery were collected for analyzing: 1. Measuring the left ventricle weight/body weight (LVW/BW), to assess the cardiac hypertrophy; 2. Comparing cell size and cardiomyocyte areas of cross sections by hematoxylin-eosin (HE) staining to judge the cardiomyocyte hypertrophy; 3. Determining the degree of collagen fiber accumulation and collagen volume fraction (CVF) by picrosirius red stained; 4. Detecting the hydroxyproline concentrations by the modified alkaline hydrolysis method, to determine the cardiac total collagen contents; Measuring the Ang-Ⅱconcentrations in cardiac and plasma by enzyme linked immunosorbent assay (ELISA); 5. The expression of connexin 43 (Cx43) was assessed by immunohistochemistry; 6. Checking the concentrations of endogenous hydrogen sulfide in plasma by methylene blue spectrophotometry.Results: 1. As compared to sham group, the left ventricle weight (LVW) and left ventricle weight/body weight (LVW/BW) of abdominal aortic coarctation rats (AAC) increase respectively 35.26% (P<0.05), 25% (P<0.05), enalapril (5mg/kg/d) administration, the LVW and LVW/BW decrease 23.4%(P<0.05), 6.38%(P<0.05) compared with AAC group, while sodium hydrosulfide(NaHS, the donor of H2S, 14umol/kg/d) administrated intraperitoneally, the LVW and LVW/BW reduce respectively 14.9% (P<0.05), 4.49% (P<0.05).2. As compared to the sham group, the cross-sections areas of cardiomyocyte in AAC rats enhances 94.59% (P<0.01), and that in the enalapril group reduces 25.48% (P<0.05) compared with AAC rats. Meanwhile, the cross section areas of the H2S group decreases 15.97% (P<0.05) compared with AAC rats.3. The collagen volume fraction (CVF) and the cardiac hydroxyproline contents in AAC rats elevate respectively 60% (P<0.05), 58% (P<0.05) compared with sham group. In the enalapril or H2S groups, the collagen densities in the subendocardial, subepicardial of the left ventricle are significantly lower than those in the AAC group. The CVF and the cardiac hydroxyproline contents in enalapril decrease respectively 24% (P<0.05), 17.9% (P<0.05) compared with AAC rats, and those in H2S rats reduce respectively 31.4% (P<0.05), 39.1% (P<0.05).4. In the cardiac tissue, the Ang-Ⅱconcentration in AAC rats increase 29.3% (P<0.05) compared with sham rats, and as compared to AAC group, the Ang-Ⅱcontents in enalapril group reduce 12.28% (P<0.05), and those in H2S group decrease 17.47% (P<0.05). While in the plasma, the concentrations of Ang-Ⅱare no significantly difference among groups (P>0.05).5. The connexin 43 is the principal connexin in the mammalian ventricle. in AAC group, it could be observed the significantly decrease in the concentrations of Cx43 as compared to the Sham group. However, enalapril administration could ameliorate the expression of connexin 43, which could be also seen in hydrogen sulfide administrated intraperitoneally rats.6. As compared to sham group, the endogenous H2S concentrations in plasma in AAC rats reduces 7.65% (P<0.05), and that in the enalapril group elevates 4.27% (P<0.05) compared with AAC rats. Meanwhile, the endogenous H2S contents in NaHS administration enhances 3.65% (P<0.05).Conclusion: 1. In the abdominal aortic coarctation rats, the left ventricle hypertrophy significantly elevate, and the degree of cardiac fibrosis obviously exacerbate. And in the enalapril (5mg/kg/d) or hydrogen sulfide (14umol/kg/d) groups, the left ventricle hypertrophy obviously ameliorate, the degree of cardiac fibrosis significantly decline. Moreover, the enalapril or H2S could ameliorate the expression of connexin43 in abdominal aortic coarctation rats. 2. The intracardiac renin-angiotensin system is activated in abdominal aortic coarctation rats, the expression of angiotensin-Ⅱis obviously up-regulated, while enalapril or H2S administration reduce the expression of Ang-Ⅱ. It is suggested that the preventing effect of H2S on cardiac hypertrophy and fibrosis may be related to intracardiac RAS, but no related to that in plasma. |
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