| Cardiovascular diseases have been threatening human health all over the world. Amongwhich, essential hypertension（EH） is the most common cardiovascular disorder clinically. Theprevalence of hypertension in adults shows a rising trend in China. In2002, the prevalence ofhypertension in Chinese population aged18years or above was18.8%, which increased to33.5%in2010, with35.1%in adult males. Recent studies have found that some EH patients presentedwith maternally inherited characteristics. Maternal inheritance is a peculiar mode of mitochondrialDNA inheritance. Fuents et al3reported that the offspring hypertension and mother hypertensionhas a significant correlation, and also, mtDNA mutations are related with elevated blood pressure,but the underlying mechanism is unclear. Based on a study with small sample size, we tried toreveal the related mechanisms how essential hypertension characterized with maternal inheritanceis caused by mitochondrial mutations.Totally115pedigrees were enrolled in this study. The subjects answered questionnaires andreceived full mitochondrial genome sequencing analysis. According to the incidence ofhypertension in three-generations of Chinese family, they were divided into maternally-inheritedEH pedigrees (group A, n=17), non-maternally-inherited EH pedigrees (group B, n=65), andnormal control pedigrees (group C, n=33). The results indicated that mitochondrial tRNA genemutation was significantly correlated with EH. Mitochondrial tRNA gene mutation occurred morefrequently in patients with EH; mtDNA A5823G, mtDNA T4386C and mtDNA C15910T mayplay important roles in the pathogenesis of maternally inherited EH; mtDNA5597deletion mayhave some relationship with EH occurrence, but may not be necessarily due to maternalinheritance.In order to clarify the relationship between mtDNA C15910T and maternally inherited EH,all maternal family members’ whole mitochondrial genome carrying the mutation from Zhuozhouand Inner Mongolia pedigrees were analyzed, and their blood biochemical indices werecompared. We found that the overall incidence rate of EH was59.3%in these maternal familymumbers, and90%in males, significantly higher than in the general population in China(33.5％);the age at onset of EH in members carrying mtDNA C15910T is earlier than in gender-andage-matched groups. The mtDNA C15910T, which is extraordinarily conserved from mollusc tohuman mitochondria, is located at D-loop of tRNAThr. It was shown that this modified C15910contributed to the structural formation and stabilization of functional tRNAThr. The mutationdestroys the base pairs and may therefore affect the function and stability of tRNAThr. The serumsodium and chloride levels were increased in members carrying mtDNA C15910T, while moresignificantly in maternal members accompanied by EH. It is suggested that mtDNA C15910Tinduced hypertension, either directly, and/or by elevating serum sodium and chloride levels. To further reveal the mechanism through which mtDNA C15910T causes maternallyinherited EH, PBMCs from Zhuozhou pedegrees were cultured in vitro. They are divided into fourgroups, hypertension matrilineal (n=6, EH+Mu), non-hypertension matrilineal (n=6, Mu),hypertension without mutation (n=6, EH), and normal controls (n=6, Con). We found that cellscarrying mtDNAC15910T were characterized by more viability and proliferation. The increasedATP production results in raised intracellular ROS. The mitochondrial dysfunction results inreduced APN levels secreted from adipose tissue, causing hypoadiponectinemia.Hypoadiponectinemia further promotes cell proliferation, which in turn produces more ROS. Thisvicious cycle promotes the occurrence of essential hypertension with maternally inherited mtDNAC15910T. The APN, AdipoR1, PGC-1α were reduced, but ERRα significantly upregulated inC15910T mutation group, indicating that the mtDNA C15910T mutation may induce hypertensionby changing APN, AdipoR1, PGC-1α or APN, ERRα signal pathway to elevate blood pressure. |
PDF Full Text Request