Effect Of Androgen Receptor Protein Expression On Vascular Remodeling In Renovascular Hypertensive Rats

Background Vascular remodeling is a prominent manifestation of hypertensive vascular damage, which is one of the researchful hotspots of hypertension in recent years.And vascular remodeling is dynamically produced, including the synthesis and release of the renin-angiotensin system, the cytokines, the growth factors and other vaoactive substances; the proliferation, hypertrophy, migration and apoptosis of cell; the synthesis, secretion, degradation and rearrangement of matrix component, which eventually changes the vessel structure. In the histomorphological, vascular remodeling shows that the blood vessel wall thickens, the smooth muscle cell is hypertrophy and disorganization, disordered arrangement of elastic fibers, its lumen diameter shorten, the ratio of middle wall thickness and lumen diameter increased, etc. From the perspective of the hemodynamics, vascular remodeling plays a vital role in maintenance and development of high blood pressure, and it has a key role in the lumen area, which promotes the development of atherosclerosis, coronary heart disease, ventricular hypertrophy, heart failure and other diseases. Therefore, to explore the molecular mechanisms of vascular remodeling of hypertension is great significance, effective prevention and reversal of vascular remodeling will bebeneficial to various cardiovascular diseases. Testosterone is an important androgen in the human body. In addition to maintaining normal male physiological function(such as inducing the formation of the male genitalia in embryonic period, promoting the development of male secondary sexual characteristics in adolescence, maintaining male reproductive function after the adolescence), testosterone affects on the glucose metabolism and lipid metabolism, protein synthesis, inflammation, erythropoietin secretion, bone density and strength, muscle growth, electrolyte excretion, etc. And most of functionality is implemented through the androgen receptor. Androgen receptor is a ligand regulated transcription factor, and it belongs to the steroid receptor in the members of the nuclear receptor superfamily. Androgen receptor mainly exists in the cytoplasm, and combines with chaperone protein(such as heat shock protein), being activated after combined with testosterone, as a transcription factor to control the transcription of target genes and the synthesis of protein, and to regulate cell growth, differentiation and proliferation. Mitogen activated protein kinases are highly conservative extracellular signaling molecules, and are widely distributed in the cytoplasm, regulate the growth, differentiation and proliferation of cell. Previous studies have shown that androgen receptor is coupled with mitogen activated protein kinase signal transduction pathway, participated in left ventricular remodeling, atherosclerosis, thrombosis, prostate cancer, ovarian cancer, breast cancer and other diseases. The mitogen activated protein kinases mainly are dephosphorylated and inactivated by phosphatase, and mitogen activated protein kinase phosphatase-1 is the most important Mitogen activated protein kinase specific negative phosphatase. In the process of vascular remodeling of hypertension, whether the expression level of androgen receptor is change, and what is the possible signal transduction mechanism? Which is few reporte.Objective To observe the change of protein expression level of androgen receptor in theaorta of renovascular hypertensive rats, and explore the impact on hypertensive vascular remodeling and the underlying mechanisms.Methods Thirty male rats were randomly allocated into there groups: the normal control group, the sham operation group and the renovascular hypertension group(10 rats in each group). The model of renovascular hypertensive rat was established using the “two- kidney and one- clip” method. The tail-cuff method to measure the systolic blood pressure, and hematoxylin and eosin staining to observe the morphological structure of aorta. Using image analysis system to measure the index of vascular remodeling: media thickness, lumen diameter, media thickness / lumen diameter, and the protein expressions of androgen receptor and mitogen activated protein kinase phosphatase-1 were detected by immunohistochemical technique.Result 1.There was no significant difference in systolic blood pressure of the normal control group at each time point(P> 0.05), there was no significant aortic vascular remodeling; 2.There was no significant difference in systolic blood pressure of the sham operation control group at each time point(P> 0.05); and also no significant difference between the normal control group and the sham operation control group in the morphological structure, and also no significant difference in the expression of androgen receptor and mitogen activated protein kinase phosphatase-1 was found between the normal control group and the sham operation control group(P>0.05); 3.There was significant difference before and after modeling in systolic blood pressure of the renovascular hypertension group(F between group = 1211.779, F time = 1613.225, F interaction = 1537.050, P <0.001; compared with the normal control group, P <0.001), Compared with the normal control group and the sham operation control group,the vascular remodeling of aorta in the renovascular hypertension group was remarkable, and the expression of androgen receptor and mitogen activated proteinkinase phosphatase-1 significantly decreased(P<0.01); 4.In the hypertensive group, the expression of androgen receptor was positively correlated with the expression of mitogen activated protein kinase phosphatase-1(r=0.657, P=0.039), and no such correlation was found in the normal control group or in the sham operation control group(r = 0.589, 0.436, P> 0.05).Conclusion 1.There is the down-regulation of androgen receptor protein expression in hypertensive vascular remodeling process, suggesting that the down-regulation of androgen receptor protein expression has an effect on hypertensive vascular remodeling; 2.The down-regulation of androgen receptor and mitogen activated protein kinase phosphatase-1 shows positive correlation in hypertensive vascular remodeling process, suggesting that the effect of androgen receptor protein on hypertensive vascular remodeling is coupled with mitogen activated protein kinase signal transduction pathway.