载脂蛋白A-I模拟肽与血管新生

血管新生能够有效改善缺血性心脏病的病生理进程,以促进血管新生为目的的治疗可能是缺血性心脏病的有效方法。正常高密度脂蛋白(high density lipoprotein,HDL)在机体内起着逆转运胆固醇、抗炎、抗氧化和促进血管新生等保护心血管的作用。作为HDL的主要功能蛋白,载脂蛋白A-I(apolipoprotein A-I,ApoA-I)在HDL的各种功能活动中起关键作用。根据ApoA-I的两亲性α-螺旋结构特点,研究人员设计了一系列旨在模拟ApoA-I功能的模拟肽。ApoA-I模拟肽在体内外实验中显示出一定的促进血管新生的能力,但其机制尚不完全清楚。对ApoA-I模拟肽在血管新生中的进一步研究可能给缺血性心脏病带来新的治疗方法。     

C-反应蛋白加速载脂蛋白E-1-小鼠的动脉粥样硬化进展

血浆C鄄反应蛋白(C鄄reactiveprotein,CRP)浓度是动脉粥样硬化形成的一个强的预告指标。但直至目前,尚乏体内研究资料说明CRP促动脉粥样硬化。方法与结果:用载脂蛋白E鄄1鄄(apoE鄄1鄄)小鼠模型观察在基础情况下或用(松节油turpentine)刺激时CRP转基因(transgene,tg)对动脉粥样硬化形成的影响。tuibcntine处理的29周龄雄小鼠的主动脉粥样病变大48%,未处理的CRP土tg+/0/apo E鄄1鄄小鼠大34%(P<0.05)。turpentine处理本身并不影响CRP转基因或不转基因apo E鄄1鄄小鼠的动脉粥样硬化的程度。转基因小鼠血浆补体3(C3)水平较低,但CRP及C…     

高血压治疗新策略:高血压抗动脉粥样硬化治疗

高血压患者降压联合降脂突破冠心病防治的瓶颈 回顾高血压治疗的历程不难发现,降压治疗可较大幅降低心力衰竭和卒中事件,但是对冠心病事件的降幅却未达预期[1];且有研究显示,即使血压已降至正常范围,其发生冠心病的风险仍显著高于常人[2].这可能是由于在高血压的早期阶段已经存在进展性的动脉粥样硬化病变.对意外死亡个体的尸检结果也证实,即使是年轻(15～34岁)的高血压患者,动脉粥样硬化的发生率已高达50%[3].     

高血压治疗新策略:高血压抗动脉粥样硬化治疗

高血压患者降压联合降脂突破冠心病防治的瓶颈 回顾高血压治疗的历程不难发现,降压治疗可较大幅降低心力衰竭和卒中事件,但是对冠心病事件的降幅却未达预期[1];且有研究显示,即使血压已降至正常范围,其发生冠心病的风险仍显著高于常人[2].这可能是由于在高血压的早期阶段已经存在进展性的动脉粥样硬化病变.对意外死亡个体的尸检结果也证实,即使是年轻(15～34岁)的高血压患者,动脉粥样硬化的发生率已高达50%[3].     

高血压治疗新策略:高血压抗动脉粥样硬化治疗

高血压患者降压联合降脂突破冠心病防治的瓶颈 回顾高血压治疗的历程不难发现,降压治疗可较大幅降低心力衰竭和卒中事件,但是对冠心病事件的降幅却未达预期[1];且有研究显示,即使血压已降至正常范围,其发生冠心病的风险仍显著高于常人[2].这可能是由于在高血压的早期阶段已经存在进展性的动脉粥样硬化病变.对意外死亡个体的尸检结果也证实,即使是年轻(15～34岁)的高血压患者,动脉粥样硬化的发生率已高达50%[3].     

高血压治疗新策略:高血压抗动脉粥样硬化治疗

高血压患者降压联合降脂突破冠心病防治的瓶颈 回顾高血压治疗的历程不难发现,降压治疗可较大幅降低心力衰竭和卒中事件,但是对冠心病事件的降幅却未达预期[1];且有研究显示,即使血压已降至正常范围,其发生冠心病的风险仍显著高于常人[2].这可能是由于在高血压的早期阶段已经存在进展性的动脉粥样硬化病变.对意外死亡个体的尸检结果也证实,即使是年轻(15～34岁)的高血压患者,动脉粥样硬化的发生率已高达50%[3].     

高血压治疗新策略:高血压抗动脉粥样硬化治疗

高血压患者降压联合降脂突破冠心病防治的瓶颈 回顾高血压治疗的历程不难发现,降压治疗可较大幅降低心力衰竭和卒中事件,但是对冠心病事件的降幅却未达预期[1];且有研究显示,即使血压已降至正常范围,其发生冠心病的风险仍显著高于常人[2].这可能是由于在高血压的早期阶段已经存在进展性的动脉粥样硬化病变.对意外死亡个体的尸检结果也证实,即使是年轻(15～34岁)的高血压患者,动脉粥样硬化的发生率已高达50%[3].     

高血压治疗新策略:高血压抗动脉粥样硬化治疗

高血压患者降压联合降脂突破冠心病防治的瓶颈 回顾高血压治疗的历程不难发现,降压治疗可较大幅降低心力衰竭和卒中事件,但是对冠心病事件的降幅却未达预期[1];且有研究显示,即使血压已降至正常范围,其发生冠心病的风险仍显著高于常人[2].这可能是由于在高血压的早期阶段已经存在进展性的动脉粥样硬化病变.对意外死亡个体的尸检结果也证实,即使是年轻(15～34岁)的高血压患者,动脉粥样硬化的发生率已高达50%[3].     

高血压治疗新策略——高血压抗动脉粥样硬化治疗

2002年全国居民营养与健康状况调查发现,我国成人高血压患病率高达18.8%,每年新增高血压患者1000万,估计2006年全国高血压患者已达2亿.高血压对人体的主要危害在于心、脑、肾等靶器官损害,高血压治疗的最终目的在于最大程度降低心脑血管病的总体风险.     

高血压治疗新策略:高血压抗动脉粥样硬化治疗

高血压患者降压联合降脂突破冠心病防治的瓶颈 回顾高血压治疗的历程不难发现,降压治疗可较大幅降低心力衰竭和卒中事件,但是对冠心病事件的降幅却未达预期[1];且有研究显示,即使血压已降至正常范围,其发生冠心病的风险仍显著高于常人[2].这可能是由于在高血压的早期阶段已经存在进展性的动脉粥样硬化病变.对意外死亡个体的尸检结果也证实,即使是年轻(15～34岁)的高血压患者,动脉粥样硬化的发生率已高达50%[3].     

Intracellular and extracellular processing of human apolipoprotein A-I: secreted apolipoprotein A-I isoprotein 2 is a propeptide.

We have recently proposed that the major secreted isoprotein form of human apolipoprotein A-I (designated apo A-I2) is modified extracellularly to become the predominant apo A-I form seen in plasma (designated apo A-I4). In the current report we demonstrate that the primary translation product of human apo A-I (designated apo A-I2p) has a 24-amino-acid NH2-terminal extension with a sequence of Met-Lys-Ala-Ala-Val-Leu-Thr-Leu-Ala-Val-Leu-Phe- Leu-Thr-Gly-Ser-Gln-Ala-Arg-His-Phe-Trp-Gln-Gln. The first 18 amino acids of this NH2-terminal extension are cleaved intracellularly by the signal peptidase, resulting in the formation of apo A-I2, which is the secreted form of apo A-I. Sequence analysis of apo A-I2 confirmed that it contains a hexapeptide extension at its NH2 terminus compared to apo A-I4. This observation demonstrates that apo A-I2 is a propeptide and that the apo A-I2 to apo A-I4 conversion involves the removal of the NH2-terminal hexapeptide of apo A-I2 by a protease in plasma, lymph, or both. Our findings indicate that apo A-I is synthesized as a prepropeptide, which undergoes intracellular and extracellular proteolysis to attain the major plasma apo A-I4 isoprotein form.     

AAV serotype-dependent apolipoprotein A-I Milano gene expression

Recent evidence from a double-blind, randomized study showed that treatment with apolipoprotein A-I Milano (ApoA-I Milano) in a complex with phospholipids produced significant regression of the coronary atheroma burden in patients with acute coronary syndromes. We previously showed similar regression of atherosclerosis in an animal model. Here, we examined a viral vector-based gene delivery system as a basis for ApoA-I Milano gene therapy. Comparing levels of expression using combinations of the cytomegalovirus (CMV) promoter in a recombinant serotype 2 adeno-associated virus (rAAV2) linked to ApoA-I Milano or the enhanced green fluorescent protein (EGFP) genes, we found that a promoter construct of two CMV core promoters sharing a CMV enhancer was more active than other combinations or a single CMV promoter. In vivo assessment of this optimal CMV construct using rAAV2 virus particles for intravenous (IV) or intramuscular (IM) routes of delivery produced high circulating levels of ApoA-I Milano protein for extended periods (up to 220 ng/ml at 22 weeks p.i.) by IV delivery while the IM route resulted in a relatively short period of very low-level ApoA-I Milano expression. Since there was no difference in the immune response between the two routes of delivery, we reasoned that tissue tropism might be responsible for this differential gene expression. To explore this possibility, we investigated the effect of different AAV serotypes on ApoA-I Milano gene expression in vivo. It found that rAAV1-mediated expression of ApoA-I Milano was approximately 15- and 9-fold higher than rAAV2 and rAAV5, respectively when IM injection routes were compared while all three AAV serotypes produced substantial levels of ApoA-I Milano expression from IV injection. These studies demonstrate that by modifying the promoter and serotype, increases in the efficiency of AAV-directed transgene expression could be achieved and support the potential of AAV-mediated gene therapy.     

High-density lipoprotein/apolipoprotein A-I infusion therapy

Strategies to decrease the progression and burden of atherosclerosis by capitalizing on the protective effect of high-density lipoprotein (HDL) and/or apolipoprotein A1 (apoA-I) levels remain active. Although efforts to raise HDL through the administration of oral agents are still being pursued, the disappointing results demonstrated with torcetrapib, an agent that elevated serum HDL and apoA-I levels through the inhibition of cholesterol ester transfer protein, have raised questions regarding this approach. An alternate strategy that consists of short-term infusions of reconstituted HDL or apoA-I is currently under evaluation. Several infusion compounds have been evaluated in clinical trials that utilize cardiovascular imaging technologies and biomarkers to assess potential clinical efficacy. Although these compounds are still in early-stage development, the results of these trials have supported the viability of this line of investigation. This review addresses the potential of HDL and/or apoA-I infusions as a possible therapeutic strategy for the treatment of coronary artery disease.     

Structural and functional properties of apolipoprotein A-I mutants.

Apolipoprotein (apo) A-I is composed of 243 amino acid residues that fold into amphipathic helixes, and plays a central role in the high density lipoprotein (HDL) metabolism. Familial apoA-I deficiency is a rare metabolic disorder of which three cases have been characterized at a molecular level in western Japan. However, in subjects with apoA-I deficiency, coronary artery disease was not always present. One apo A-I deficiency was compound heterozygous apoA-I mutant for a TATA box mutation and a structural nonsense mutation. To date, screening analysis in our laboratory has identified nine genetically-determined structural mutations of apo A-I. We have also characterized these apo A-I mutations, including apoA-I (Glu235del) Nichinan. Few structural mutations were associated with altered HDL cholesterol levels.     

Metabolism of apolipoprotein A-I in healthy young adults.

The metabolism of 125I-labeled apolipoprotein A-I bound to high-density lipoproteins by an in vitro transfer procedure was studied in 10 healthy young adults (5 males and 5 females). Both sexes handled the labeled apolipoprotein similarly, and no statistically significant differences were found in the derived kinetic data. The mean (+/- 1 SD) plasma apolipoprotein A-I concentrations (males, 105 +/- 19 mg/dl; females, 111 +/- 13.8 mg/dl) and half-lives (males, 4.46 +/- 0.45 days; females, 4.64 +/- 0.70 days) were similar, as were the fractional rates of catabolism (FCR) of the apoprotein derived from the above data (FCR in males, 27% of intravascular pool/day; FCR in females, 25% of intravascular pool/day). The absolute catabolic rate of the apoprotein, equivalent under steady-state conditions to the synthetic rate, was 12.1 +/- 1.6 mg/kg/day in males and 11.9 +/- 2.4 mg/kg/day in females.     

Structure,function and amyloidogenic propensity of apolipoprotein A-I

Apolipoprotein A-I, the major structural apolipoprotein of high-density lipoproteins, efficiently protects humans from cholesterol accumulation in tissues; however, it can cause systemic amyloidosis in the presence of peculiar amino acid replacements. The wild-type molecule also has an intrinsic tendency to generate amyloid fibrils that localise within the atherosclerotic plaques. The structure, folding and metabolism of normal apolipoprotein A-I are extremely complex and as yet not completely clarified, but their understanding appears essential for the elucidation of the amyloid transition.

We reviewed present knowledge on the structure, function and amyloidogenic propensity of apolipoprotein A-I with the aim of highlighting the possible molecular mechanisms that might contribute to the pathogenesis of this disease. Important clues on apolipoprotein A-I amyloidogenesis may be obtained from classical comparative studies of the properties of the wild-type versus the amyloidogenic counterpart. Additionally, in the case of apoA-I, further insights on the molecular mechanisms underlying its amyloidogenic propensity may derive from comparative studies between amyloidogenic variants and other mutations associated with hypoalphalipoproteinemia without amyloidosis.     

Formation and metabolism of prebeta-migrating, lipid-poor apolipoprotein A-I

The preferred extracellular acceptor of cell phospholipids and unesterified cholesterol in the process mediated by the ATP-binding cassette A1 (ABCA1) transporter is a monomolecular, prebeta-migrating, lipid-poor or lipid-free form of apolipoprotein (apo) A-I. This monomolecular form of apoA-I is quite distinct from the prebeta-migrating, discoidal high-density lipoprotein (HDL) that contains two or three molecules of apoA-I per particle and which are present as minor components of the HDL fraction in human plasma. The mechanism of the ABCA1-mediated efflux of phospholipid and cholesterol from cells has been studied extensively. In contrast, much less attention has been given to the origin and subsequent metabolism of the acceptor lipid-free/lipid-poor apoA-I. There is a substantial body of evidence from studies conducted in vitro that a monomolecular, lipid-free/lipid-poor form of apoA-I dissociates from HDL during the remodeling of HDLs by plasma factors such as cholesteryl ester transfer protein, hepatic lipase, and phospholipid transfer protein. The rate at which apoA-I dissociates from HDL is influenced by the phospholipid composition of the particles and by the presence of apoA-II. This review describes current knowledge regarding the formation, metabolism, and regulation of monomolecular, lipid-free/lipid-poor apoA-I in plasma.