Yuqi Liu

Maternally Inherited Essential Hypertension Is Associated With the Novel 4263A>G Mutation in the Mitochondrial tRNAIle Gene in a Large Han Chinese Family

Rational: Despite maternal transmission of hypertension in some pedigrees, pathophysiology of maternally inherited hypertension remains poorly understood. Objective: To establish a causative link between mitochondrial dysfunction and essential hypertension. Method and Results: A total of 106 subjects from a large Chinese family underwent clinical, genetic, molecular, and biochemical evaluations. Fifteen of 24 adult matrilineal relatives exhibited a wide range of severity in essential hypertension, whereas none of the offspring of affected fathers had hypertension. The age at onset of hypertension in the maternal kindred varied from 20 years to 69 years, with an average of 44 years. Mutational analysis of their mitochondrial genomes identified a novel homoplasmic 4263A>G mutation located at the processing site for the tRNAIle 5′-end precursor. An in vitro processing analysis showed that the 4263A>G mutation reduced the efficiency of the tRNAIle precursor 5′-end cleavage catalyzed by RNase P. tRNA Northern analysis revealed that the 4263A>G mutation caused ≈46% reduction in the steady-state level of tRNAIle. An in vivo protein-labeling analysis showed ≈32% reduction in the rate of mitochondrial translation in cells carrying the 4263A>G mutation. Impaired mitochondrial translation is apparently a primary contributor to the reductions in the rate of overall respiratory capacity, malate/glutamate-promoted respiration, succinate/glycerol-3-phosphate-promoted respiration, or N,N,N′,N′-tetramethyl-p-phenylenediamine/ascorbate–promoted respiration and the increasing level of reactive oxygen species in cells carrying the 4263A>G mutation. Conclusions: These data provide direct evidence that mitochondrial dysfunction caused by mitochondrial tRNAIle 4263A>G mutation is involved in essential hypertension. Our findings may provide new insights into pathophysiology of maternally transmitted hypertension.

Mitochondrial Transfer RNAMet 4435A>G Mutation Is Associated With Maternally Inherited Hypertension in a Chinese Pedigree

Mitochondrial DNA mutations have been associated with cardiovascular disease. We report here the clinical, genetic, and molecular characterization of 1 Han Chinese family with suggestively maternally transmitted hypertension. Matrilineal relatives in this family exhibited the variable degree of hypertension at the age at onset of 44 to 55 years old. Sequence analysis of entire mitochondrial DNA in this pedigree identified the known homoplasmic 4435A>G mutation, which is located immediately at the 3 prime end to the anticodon, corresponding with the conventional position 37 of tRNAMet, and 35 other variants belonging to the Asian haplogroup B5a. The adenine (A37) at this position of tRNAMet is extraordinarily conserved from bacteria to human mitochondria. This modified A37 was shown to contribute to the high fidelity of codon recognition, the structural formation, and stabilization of functional tRNAs. In fact, a 40% reduction in the levels of tRNAMet was observed in cells carrying the 4435A>G mutation. As a result, a failure in mitochondrial tRNA metabolism, caused by the 4435A>G mutation, led to ≈30% reduction in the rate of mitochondrial translation. However, the homoplasmic form, mild biochemical defect, and late onset of hypertension in subjects carrying the 4435A>G mutation suggest that the 4435A>G mutation itself is insufficient to produce a clinical phenotype. The other modifier factors, such as nuclear modifier genes, environmental, and personal factors may also contribute to the development of hypertension in the subjects carrying this mutation. Our findings imply that the 4435A>G mutation may act as an inherited risk factor for the development of hypertension in this Chinese pedigree.

Failures in Mitochondrial tRNAMet and tRNAGln Metabolism Caused by the Novel 4401A>G Mutation Are Involved in Essential Hypertension in a Han Chinese Family

We report here on the clinical, genetic, and molecular characterization of 1 Han Chinese family with maternally transmitted hypertension. Three of 7 matrilineal relatives in this 4-generation family exhibited the variable degree of essential hypertension at the age at onset, ranging from 35 to 60 years old. Sequence analysis of the complete mitochondrial DNA in this pedigree identified the novel homoplasmic 4401A>G mutation localizing at the spacer immediately to the 5′ end of tRNAMet and tRNAGln genes and 39 other variants belonging to the Asian haplogroup C. The 4401A>G mutation was absent in 242 Han Chinese controls. Approximately 30% reductions in the steady-state levels of tRNAMet and tRNAGln were observed in 2 lymphoblastoid cell lines carrying the 4401A>G mutation compared with 2 control cell lines lacking this mutation. Failures in mitochondrial metabolism are apparently a primary contributor to the reduced rate of mitochondrial translation and reductions in the rate of overall respiratory capacity, malate/glutamate-promoted respiration, succinate/glycerol-3-phosphate–promoted respiration, or N,N,N′,N′-tetramethyl-p-phenylenediamine/ascorbate-promoted respiration in lymphoblastoid cell lines carrying the 4401A>G mutation. The homoplasmic form, mild biochemical defect, late onset, and incomplete penetrance of hypertension in this family suggest that the 4401A>G mutation itself is insufficient to produce a clinical phenotype. Thus, the other modifier factors, eg, nuclear modifier genes and environmental and personal factors, may also contribute to the development of hypertension in these subjects carrying this mutation. These data suggest that mitochondrial dysfunctions, caused by the 4401A>G mutation, are involved in the development of hypertension in this Chinese pedigree.

Efficacy and safety of limus-eluting versus paclitaxel-eluting coronary artery stents in patients with diabetes mellitus: A meta-analysis

BACKGROUND/OBJECTIVES The relative efficacy and safety of limus-eluting stent (LES) versus paclitaxel-eluting stent (PES) in DM patients remain unclear. METHODS The PubMed, EMBASE, and Cochrane Central Register of Controlled Trials electronic databases were searched from January 2001 to December 2013. Clinical trials that performed head-to-head comparisons of LES versus PES implantation in patients with DM were considered for inclusion. RESULTS This meta-analysis included 28 clinical trials involving 23,678 patients: 9953 who underwent sirolimus-eluting stent (SES) implantation, 4209 underwent everolimus-eluting stent (EES) or zotarolimus-eluting stent (ZES) implantation, and 9516 underwent PES implantation. The short-term target lesion revascularization (TLR) rate was significantly lower after SES implantation than after PES implantation (3.6% vs 6.3%; odds ratio (OR): 0.659; P=0.014), but there were no significant differences in the rates of target vessel revascularization (TVR), stent thrombosis (ST), myocardial infarction (MI), all-cause mortality, or major adverse cardiac events (MACE). There were no differences in the longer-term rates of TLR, TVR, ST, MI, all-cause mortality, or MACE between SES versus PES. Second-generation LES (EES or ZES) implantation resulted in lower rates of ST (2.1% vs 3.3%; OR: 0.586; P<0.001), MI (2.3% vs 4.1%; OR: 0.527; P=0.001), and MACE (8.0% vs 10.3%; OR: 0.796; P=0.007) than PES implantation. CONCLUSIONS In patients with DM, short- and longer-term MACE rates were similar after first-generation LES and PES implantation. The second-generation LES may be better than PES implantation in rates of ST, MI, and MACE.

Mitochondrial tRNA mutations in Chinese hypertensive individuals.

PURPOSE Hypertension is a very important risk factor for cardiac vascular disease. The previous studies showed that mitochondrial DNA mutations are associated with cardiovascular disease, including hypertension. METHODS In this study we did systematical analysis on the total 22 mitochondrial tRNAs and the clinical, genetic and molecular changes of 140 Chinese hypertension and 124 controls. RESULTS This analysis identified 22 nucleotide changes among 15 different tRNA genes. There are 15 mutations with CI (Conservation index) larger than 75%. Of these, there are 26 patients with CI larger than 75% in the HTN group, higher than the 6 subjects in the control group (P=0.00). The tRNA(Phe) G586A, tRNA(Lys) G8313A and tRNA(His) G12147A mutations create highly conservative base-pairings on the D-stem, tRNA(Lys) G8342A on the T-stem, tRNA(Phe) T616C, tRNA(Ala) T5628C, tRNA(Tyr) G5856A and tRNA(Thr) A15924G on the AC stem, tRNA(Leu(CUN)) G12300A on the AC loop, tRNA(Met) C4467T, tRNA(Trp) T5578C, tRNA(Lys) A8296G, tRNA(Arg) T10463C and tRNA(Thr) C15891T on ACC stem, and tRNA(Ser(UCN)) C7492T on D-A junction, while the other tRNA variants were polymorphisms. The pedigrees of PLAH78 carrying the T5578C, PLAH84 carrying the C4467T, PLAH60 carrying the T5628C and PLAH118 carrying the C7492T mutation exhibited maternal transmission of essential hypertension. Sequence analysis of their mitochondrial genomes revealed the presence of T5578C, C4467T, T5628C or C7492T mutations but the absence of other functionally significant mutations in all matrilineal relatives of these families. CONCLUSIONS These tRNAs mutations, associated with altered structures of tRNAs and mitochondrial dysfunction, may contribute to the hypertension in Chinese population. A lot of work still should be done for the mechanism and functional effect of the mtDNA mutation on hypertension.

Percutaneous coronary intervention in the elderly with ST-segment elevation myocardial infarction

As a result of increased life expectancy, octogenarians constitute an increasing proportion of patients admitted to hospital for ST-segment elevation myocardial infarction (STEMI). Primary percutaneous coronary intervention is currently the treatment of choice for octogenarians presenting with STEMI. The recent literature on this topic has yielded controversial results, even though advances in drug-eluting stents and new types of antithrombotic agents are improving the management of STEMI and postoperative care. In this paper, we review the current status of percutaneous coronary intervention in the elderly with STEMI, including the reasons for their high mortality and morbidity, predictors of mortality, and strategies to improve outcomes.

Voltage-dependent anion channel involved in the mitochondrial calcium cycle of cell lines carrying the mitochondrial DNA A4263G mutation

In this study, we investigated the effects of the voltage-dependent anion channel (VDAC) on the mitochondrial calcium cycle in cell lines carrying the mitochondrial DNA A4263G mutation. We established lymphoblastoid cell lines from three symptomatic individuals and one asymptomatic individual from the large Chinese Han family carrying the A4263G mutation; these were compared with three control cell lines. The mitochondrial Ca(2+) concentration and membrane potential were detected by loading cells with Rhod-2 and JC-1, respectively. Confocal images showed the average Rhod-2 and JC-1 fluorescence levels of individuals carrying the tRNA(Ile) A4263G mutation were lower than those of the control group (P<0.05). The baseline Rhod-2 fluorescence in the control group increased after exposure to atractyloside (an opener of the adenine nucleotide translocator, P<0.05), but no significant change was detected in the cell line harboring the A4263G mutation (P>0.05). The baseline JC-1 fluorescence in both the mutated and control cell lines decreased after subsequent exposure to atractyloside (P<0.05), whereas this effect of atractyloside was inhibited by Cyclosporin A (CsA, a VDAC blocker). We conclude that the mitochondrial VDAC is involved in both the increase of mitochondrial permeability to Ca(2+) and the decrease of mitochondrial membrane potential in cell lines carrying the mtDNA A4263G mutation.

The mitochondrial calcium uniporter is involved in mitochondrial calcium cycle dysfunction: Underlying mechanism of hypertension associated with mitochondrial tRNA(Ile) A4263G mutation.

Recent studies have shown that the mitochondrial DNA mutations are involved in the pathogenesis of hypertension. Our previous study identified mitochondrial tRNA(Ile) A4263G mutation in a large Chinese Han family with maternally-inherited hypertension. This mutation may contribute to mitochondrial Ca(2+) cycling dysfuntion, but the mechanism is unclear. Lymphoblastoid cell lines were derived from hypertensive and normotensive individuals, either with or without tRNA(Ile) A4263G mutation. The mitochondrial calcium ([Ca(2+)]m) in cells from hypertensive subjects with the tRNA(Ile) A4263G mutation, was lower than in cells from normotension or hypertension without mutation, or normotension with mutation (P<0.05). Meanwhile, cytosolic calcium ([Ca(2+)]c) in hypertensive with mutation cells was higher than another three groups. After exposure to caffeine, which could increase the [Ca(2+)]c by activating ryanodine receptor on endoplasmic reticulum, [Ca(2+)]c/[Ca(2+)]m increased higher than in hypertensive with mutation cells from another three groups. Moreover, MCU expression was decreased in hypertensive with mutation cells compared with in another three groups (P<0.05). [Ca(2+)]c increased and [Ca(2+)]m decreased after treatment with Ru360 (an inhibitor of MCU) or an siRNA against MCU. In this study we found decreased MCU expression in hypertensive with mutation cells contributed to dysregulated Ca(2+) uptake into the mitochondria, and cytoplasmic Ca(2+) overload. This abnormality might be involved in the underlying mechanisms of maternally inherited hypertension in subjects carrying the mitochondrial tRNA(Ile) A4263G mutation.

Effect of mitochondrial tRNALys mutation on the clinical and biochemical characteristics of Chinese essential hypertensive subjects

Mitochondrial dysfunction has been potentially implicated in both human and experimental hypertension. We performed the mutational analysis of tRNA(Lys) gene by PCR amplification and subsequent sequence analysis of the PCR fragments from 990 Chinese essential hypertensive subjects. We also made a comparative analysis of the collected data of the essential hypertension subjects who carried tRNA(Lys) mutation and those who did not carry the mutation using the methods of 1:1 case-control study. We totally found 7 mutation sites in 10 subjects. The onset ages of the individuals carrying the mutation were earlier than those who did not bear them. The level of blood urea nitrogen in hypertension subjects who carried tRNA(Lys) mutation was higher than the hypertension subjects who did not carried tRNA(Lys) mutation, while the serum potassium was significantly lower. The level of platelet count in hypertension subjects who carried tRNA(Lys) mutation was lower. The level of ventricular septal thickness in hypertension subjects who carried tRNA(Lys) mutation was higher and the level of left ventricular end diastolic diameter in hypertension subjects was significantly lower. Mitochondrial tRNA(Lys) mutations might result in the change of their structure and function, and then damaged the blood metabolism, the balance of the blood electrolyte, the steady-state of the blood cells and the heart structure and function, which were involved in the progress of the essential hypertension. Part of the essential hypertension patients clinically presented the characters of maternal inheritance, which might be associated with the tRNA(Lys) mutation.

Molecular characterization of a Chinese family carrying a novel C4329A mutation in mitochondrial tRNAIle and tRNAGln genes

BackgroundHypertension is a very common cardiovascular disease influenced by multiple genetic and environmental factors. More recently, there are some studies showed that mutations in mitochondrial DNA have been involved in its pathogenesis. In this study we did further investigations on this relationship.MethodsEpidemiological research found a Han Chinese family with probable maternally transmitted hypertension. Sequence analysis of the whole mitochondrial DNA was detected from all the family members. And evaluations of the clinical, genetic and molecular characterization were also performed.ResultsMatrilineal relatives within the family exhibited varying degrees of hypertension with an onset age of 48–55 years. Sequence analysis of this pedigree showed a novel homoplasmic 4329C > G mutation located at the 3’ end of the tRNAIle and tRNAGln genes that was absent from 366 Chinese controls. The cytosine (C) at 4329 position was very important in the structural formation and stabilization of functional tRNAs, which was highly conserved in mitochondria of various organisms and also contributed to the high fidelity of the acceptor arm. Cells carrying this mutation were also shown to harbor mitochondrial dysfunctions.ConclusionsThe C4329G point mutation in tRNAIle and tRNAGln was involved in the pathogenesis of hypertension, perhaps in association with other modifying factors.