Molecular Mechanisms Of Resistin-induced Hypertension In Mice

As a disease with highest morbidity and mortality in the world, cardiovascular disease becomes most popular research field among the scientists. And hypertension is one of the most important risk factors of cardiovascular disease. Many clinic tests show the higher morbidity rate in diabetes subjects than normal people. Meanwhile, the researches in molecular level demonstrate the correlativity between type II diabetes and cardiovascular disease.Resistin, as an important factor during the procedure of insulin resistance, has been found at a very high circulating level in cardiovascular disease subject which makes it one of the most important factors in the research of the correlativity between diabetes and cardiovascular disease. Increasing researches in recent years have demonstrated that resistin is closely relative to the inflammation related atherosclerosis, impairment of insulin-evoked vasodilation in insulin-resistance state or endothelial dysfunction. However, the direct study of relationship between resistin and hypertension and its molecular mechanism is not much.Our study is to use mouse non-invasive blood pressure system-tail cuff method to measure mouse blood pressure after 6 days injection of resistin to investigate effect of resistin on inducing mice hypertension. Then by introducing TLR4 knock-out mouse model and intragastric administration of ACE inhibitor perindopril, we use biotechnologies like RT-PCR, ELSIA, ChIP and so on to study the molecular mechanisms behind the effect of resistin on inducing hypertension in mice. In addition, we combine the serum test in normal people, diabetes subjects, hypertension subjects and the subjects suffered from both diabetes and hypertension to further investigate the correlativity between resistin, diabetes and hypertension. Our results are as follows:1. After 6 days injection of resistin, wild type C57 mice have resulted in hypertension and insulin resistance, whereas this induction of resistin have been impaired in TLR4 knock-out mice.2. By studying the three classical systems (i.e. RAS, NOS system, ET-1 system) which have important effects on regulation of blood pressure, we notice resistin is able to up-regulate the expression of Agt which is the precursor of ANG Ⅱ , activate RAS, which, however, can also be impaired in TLR4 knock-out mice. Meanwhile, our data shows the effect of resistin on hypertension in mice could be impaired by intragastric administration of ACE inhibitor perindopril.3. The results of RT-PCR and ChIP demonstrate that resistin could up-regulate Agt expression through up-regulating P65 expression and activating NF-κB pathway via TLR4.4. Human serum test demonstrates that circulating resistin level is higher in diabetes, hypertension and the subject both have diabetes and hypertension compared to the normal people. The correlation analysis shows that after being standardized by weight and age, circulating resistin level in human is positively correlative with systolic blood pressure, blood glucose, serum insulin levels and HOMA-IR.