PCSK9 deficiency rewires heart metabolism and drives heart failure with preserved ejection fraction.
PCSK9 deficiency rewires heart metabolism and drives heart failure with preserved ejection fraction.
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PCSK9缺乏症改变了心脏新陈代谢，并导致射血分数保留的心力衰竭。
DOI：
10.1093/eurheartj/ehab431
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发表时间：
2021-08-21
影响因子：
39.3
通讯作者：
Norata GD
中科院分区：
文献类型：
--
作者：
Da Dalt L;Castiglioni L;Baragetti A;Audano M;Svecla M;Bonacina F;Pedretti S;Uboldi P;Benzoni P;Giannetti F;Barbuti A;Pellegatta F;Indino S;Donetti E;Sironi L;Mitro N;Catapano AL;Norata GD
PCSK 9主要由肝脏分泌到循环中，并与低密度脂蛋白受体（LDLR）同源和非同源受体（包括CD 36）相互作用，从而促进其细胞内降解。由于PCSK 9缺乏增加脂质和脂蛋白受体的表达，从而导致细胞脂质蓄积，我们研究了这是否会影响心脏代谢和功能。 用标准脂肪饮食喂养野生型（WT）、Pcsk 9 KO、肝脏条件性Pcsk 9 KO和Pcsk 9/Ldlr双KO雄性小鼠20周，然后评价运动阻力、肌肉力量和心脏特征。Pcsk 9 KO表现出跑步阻力降低，同时伴有超声心动图异常，提示心力衰竭伴射血分数保留（HFpEF）。与WT小鼠相比，在最大偶联和非偶联呼吸后，Pcsk 9 KO小鼠的心脏线粒体活性降低，并与心脏代谢的主要变化以及LDLR和CD 36表达增加和脂质蓄积相关。在Pcsk 9/Ldlr DKO中观察到相似的表型，因此排除了LDLR对Pcsk 9 KO小鼠中观察到的心脏损害的贡献。肝脏选择性Pcsk 9 KO模型的心脏功能分析进一步排除了循环PCSK 9参与HFpEF的发生，指出了局部产生的PCSK 9的可能作用。与之一致的是，PCSK 9的R46 L功能丧失变体的携带者与匹配的对照受试者相比，左心室质量增加，但射血分数相似。PCSK 9缺乏以LDLR非依赖性方式影响心脏脂质代谢，并促进HFpEF的发生。 Pcsk 9缺陷对心脏功能和线粒体代谢的影响pcsk 9缺乏与心脏左心室厚度增加和跑步能力降低相关，与骨骼肌改变无关。电子显微镜分析显示，与线粒体嵴密度降低相关的脂滴心脏蓄积增加;这在PCSK 9 KO心脏中可导致氧化磷酸化和线粒体代谢受损。
PCSK9 is secreted into the circulation, mainly by the liver, and interacts with low-density lipoprotein receptor (LDLR) homologous and non-homologous receptors, including CD36, thus favouring their intracellular degradation. As PCSK9 deficiency increases the expression of lipids and lipoprotein receptors, thus contributing to cellular lipid accumulation, we investigated whether this could affect heart metabolism and function. Wild-type (WT), Pcsk9 KO, Liver conditional Pcsk9 KO and Pcsk9/Ldlr double KO male mice were fed for 20 weeks with a standard fat diet and then exercise resistance, muscle strength, and heart characteristics were evaluated. Pcsk9 KO presented reduced running resistance coupled to echocardiographic abnormalities suggestive of heart failure with preserved ejection fraction (HFpEF). Heart mitochondrial activity, following maximal coupled and uncoupled respiration, was reduced in Pcsk9 KO mice compared to WT mice and was coupled to major changes in cardiac metabolism together with increased expression of LDLR and CD36 and with lipid accumulation. A similar phenotype was observed in Pcsk9/Ldlr DKO, thus excluding a contribution for LDLR to cardiac impairment observed in Pcsk9 KO mice. Heart function profiling of the liver selective Pcsk9 KO model further excluded the involvement of circulating PCSK9 in the development of HFpEF, pointing to a possible role locally produced PCSK9. Concordantly, carriers of the R46L loss-of-function variant for PCSK9 presented increased left ventricular mass but similar ejection fraction compared to matched control subjects. PCSK9 deficiency impacts cardiac lipid metabolism in an LDLR independent manner and contributes to the development of HFpEF. Impact of Pcsk9 deficiency on cardiac function and mitochondrial metabolism. Pcsk9 deficiency is associated with increased heart left ventricular thickness and reduced running performance independently of skeletal muscle alterations. Electron microscopy analysis showed increased cardiac accumulation of lipid droplets associated with a reduced density of mitochondrial cristae; this proffunctionally translated into impaired oxidative phosphorylation and mitochondrial metabolism in PCSK9 KO hearts.
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影响因子：
20.1
作者：
Doenst T;Nguyen TD;Abel ED
通讯作者：
Abel ED
影响因子：
24
作者：
Santos, Raul D.;Stein, Evan A.;Raal, Frederick J.
通讯作者：
Raal, Frederick J.
影响因子：
4.8
作者：
Sharma, S;Adrogue, JV;Taegtmeyer, H
通讯作者：
Taegtmeyer, H
影响因子：
15.9
作者：
Son, Ni-Huiping;Yu, Shuiqing;Goldberg, Ira J.
通讯作者：
Goldberg, Ira J.
影响因子：
3.7
作者：
Canuel M;Sun X;Asselin MC;Paramithiotis E;Prat A;Seidah NG
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Seidah NG