The Mechanism Of Target Organs Damage Of Hypertension By Mitochondrial Structure And Function Change

Background:Essential hypertension (EH) is the most common cardiovascular disease with serious harm to human health, which is also an independent risk factor for stroke, coronary heart disease, heart failure and renal failure. In recently, the incidence of EH is increasing rapidly, genetic and environmental factors play an important role in target organs damage of hypertention. Genetically, more attention had been focused on the effect of mitochondrial gene mutation in the hypertension. Among environmental factors, high salt plays an important role in the regulation of heart, brain, kidney function. Mitochondrial not only provides important energy for cells live, but also take part in cell signal transduction and apoptosis regulation. Therefore, it is important for prevention of target organs damage to study the mechanism of target organs damage caused by mitochondrial structure and function change.Part One. Clinical Characteristics and genetic analysis of maternally inherited hypertension pedigrees with target organs damageObjective:In recent years, studies have shown that mitochondrial DNA mutation (mtDNA) could lead to mitochondrial dysfunction and was playing more and more important role in the pathogenesis of hypertension, which was characterized by maternal inheritance. Therefore this study aimed to analyze clinical data of maternal inheritance hypertension with target organs damage and genetic characteristics. Methods:140 cases of patients with essential hypertension and 124 cases of heathy control were recruited. The clinical data and mitochondrial gene sequencing were analyzed.Results:In 140 cases of patients,49 patients (35%) were characterized with maternal inheritance hypertension. Maternal inheritance is a special model for mtDNA transfer. Compare to non-maternal inheritance hypertension, LVMI of maternal inheritance hypertension was increased significantly, while EF was reduced significantly. But there was no obvious difference in terms of BMI, BP, creatinine and creatinine clearance. Maternally inherited hypertension was associated with age, smoking, alcohol consumption, high salt diet. One of these mitochondrial gene 4329 C>G mutations were associated with the pathogenesis of hypertension.Conclusion:Mitochondrial gene mutation plays an important role in the maternal inheritance hypertension, environmental factors for age, smoking, drinking, high salt also have a certain correlation.Part Two. The Mechanism of Target Organs Damage of Hypertension by Mitochondrial structure and function changeObjective:To study the effects of mitochondrial structure and function change on target organs damage in hypertensive rats.Methods:This study included four groups, as WKY control group, SHR group, SHR with mtDNA mutations group(SHR+Mu), SHR with high salt stimulation group (SHR +Nacl). The blood, urine indexes and the echocardiographic examination were performed. Electron-microscopic was used to observe the mitochondrial structure of heart, brain and kidney. The expression levels of VDAC1 and BAX in heart, brain and kidney respectively were detected by Q-PCR and Western Blotting. Immunofluorescence staining was userd to evaluate the ROS and the co-localization of VDAC1 and BAX.Results:(1) mtDNA sequence analysis was performed. The results showed that 8 SHR rats carried 14 tRNA mutations. (2) Blood pressure, urine protein, urine trace albumin, serum creatinine, blood uric acid, blood urea, white blood cells of all hypertension groups were significantly higher than that of control group, especially in SHR+Nacl group. While body weight, urine creatinine of all hypertention groups was significantly lower than that of the control group. (3) IVS、LVAW (d/s)、LVAWs、LVPWs、LVIDs、 LV Mass、LV Vol s in all hypertension groups were increased significantly than that of control group. But EF, FS were reduced significantly. LVMI of SHR+Mu group and SHR+Nacl group was increased significantly than that of SHR group. But EF was reduced significantly. (4) HE staining showed that myocardial cell hypertrophy interstitial fibrosis and inflammatory cell infiltration in heart; glomerular sclerosis, interstitial fibrosis in kidney tissue in all hypertension groups. (5) The mitochondria of the heart, brain, kidney from all hypertension groups appeared different degrees of vacuolization and structure disorder, more severe in SHR+Mu group and SHR+Nacl group. (6) ROS level of heart, brain, kidney of all hypertension groups was significantly higher than that of control group. Especially ROS level in SHR+Mu group and SHR +Nacl group increased significantly than the other groups. (7) VDAC 1, BAX expression level and interactions of heart, kidney and brain tissue in all hypertension groups were significantly higher than that of the control group, especially in SHR+Mu group and SHR+Nacl group. But there was no difference in brain of all hypertention groups.Conclusion:(1) Mitochondria plays an important role in hypertension target organs damage. Damage of mitochondria structure increases ROS level. As over expression of VDAC1 and BAX, co-localization of VDAC1 and BAX protein could contribute to heart, kidney, brain damage. (2) High salt stimulation is one of the environment factors promoting target organs damage of hypertension through above mechanism. (3) Mitochondrial gene mutations may also affect the mitochondrial structure and function, promoting target organ damage.