Integrated Omic Analysis of a Guinea Pig Model of Heart Failure and Sudden Cardiac Death

Here, we examine
key regulatory pathways underlying the transition
from compensated hypertrophy (HYP) to decompensated heart failure
(HF) and sudden cardiac death (SCD) in a guinea pig pressure-overload
model by integrated multiome analysis. Relative protein abundances
from sham-operated HYP and HF hearts were assessed by iTRAQ LC–MS/MS.
Metabolites were quantified by LC–MS/MS or GC–MS. Transcriptome
profiles were obtained using mRNA microarrays. The guinea pig HF proteome
exhibited classic biosignatures of cardiac HYP, left ventricular dysfunction,
fibrosis, inflammation, and extravasation. Fatty acid metabolism,
mitochondrial transcription/translation factors, antioxidant enzymes,
and other mitochondrial procsses, were downregulated in HF but not
HYP. Proteins upregulated in HF implicate extracellular matrix remodeling,
cytoskeletal remodeling, and acute phase inflammation markers. Among
metabolites, acylcarnitines were downregulated in HYP and fatty acids
accumulated in HF. The correlation of transcript and protein changes
in HF was weak (R2 = 0.23), suggesting
post-transcriptional gene regulation in HF. Proteome/metabolome integration
indicated metabolic bottlenecks in fatty acyl-CoA processing by carnitine
palmitoyl transferase (CPT1B) as well as TCA cycle
inhibition. On the basis of these findings, we present a model of
cardiac decompensation involving impaired nuclear integration of Ca2+ and cyclic nucleotide signals that are coupled to mitochondrial
metabolic and antioxidant defects through the CREB/PGC1α transcriptional
axis.

本研究通过整合多组学分析，在豚鼠压力超负荷模型中探究代偿性心肌肥厚（compensated hypertrophy, HYP）进展为失代偿性心力衰竭（heart failure, HF）以及心源性猝死（sudden cardiac death, SCD）过程中的关键调控通路。采用同位素标记相对和绝对定量（isobaric tags for relative and absolute quantitation, iTRAQ）联合液相色谱-串联质谱（liquid chromatography-tandem mass spectrometry, LC–MS/MS）技术，对假手术组、代偿性心肌肥厚（HYP）组与心力衰竭（HF）组的心脏组织进行相对蛋白丰度检测。代谢物分别通过液相色谱-串联质谱（LC–MS/MS）或气相色谱-质谱联用（gas chromatography-mass spectrometry, GC–MS）技术完成定量。转录组表达谱通过mRNA微阵列技术获取。豚鼠心力衰竭（HF）蛋白质组呈现出心肌肥厚（HYP）、左心室功能障碍、纤维化、炎症及血管外渗的典型生物特征。脂肪酸代谢、线粒体转录/翻译因子、抗氧化酶及其他线粒体相关过程在心力衰竭（HF）组中呈下调趋势，但在代偿性心肌肥厚（HYP）组中未出现该变化。心力衰竭（HF）组中上调的蛋白主要涉及细胞外基质重塑、细胞骨架重塑以及急性期炎症标志物相关通路。代谢物层面，酰基肉碱在代偿性心肌肥厚（HYP）组中呈下调趋势，而脂肪酸则在心力衰竭（HF）组中出现蓄积。心力衰竭（HF）组中转录本与蛋白表达变化的相关性较弱（R²=0.23），提示该过程存在转录后基因调控机制。蛋白质组与代谢组整合分析显示，肉碱棕榈酰转移酶1B（carnitine palmitoyl transferase 1B, CPT1B）介导的脂酰辅酶A代谢过程存在代谢瓶颈，同时存在三羧酸循环（TCA cycle）抑制现象。基于上述研究结果，本研究提出了一种心肌失代偿模型：该模型中Ca²⁺与环核苷酸信号的核整合过程受损，并通过cAMP应答元件结合蛋白（cAMP response element-binding protein, CREB）/过氧化物酶体增殖物激活受体γ共激活因子1α（peroxisome proliferator-activated receptor gamma coactivator 1-alpha, PGC1α）转录轴与线粒体代谢及抗氧化功能缺陷相关联。