Chen Chao-Yi, Leu Jyh-Gang, Lin Kuan-Yu, Shih Chin-Yu, Liang Yao-Jen
Graduate Institute of Applied Science and Engineering, Fu-Jen Catholic University, New Taipei City 242062, Taiwan.
Department and Institute of Life Science, Fu-Jen Catholic University, New Taipei City 242062, Taiwan.
Asian Biomed (Res Rev News). 2022 Apr 29;16(2):79-87. doi: 10.2478/abm-2022-0010. eCollection 2022 Apr.
In patients with heart failure, interleukin-18 (IL-18) levels increase in the circulatory system and injured myocardial tissue. Serotonin (5-hydroxytryptamine) receptors subtype 2B (HTR2B) play an essential role in cardiac function and development, and their overexpression in rats leads to myocardial hypertrophy. Epigallocatechin gallate (EGCG) is cardioprotective in myocardial ischemia-reperfusion injury in rats and can prevent pressure overload-mediated cardiac hypertrophy in vivo. Mice deficient in peroxisome proliferator-activated receptor delta (PPARδ) can have cardiac dysfunction, myocardial hypertrophy, and heart failure. Matrix metalloproteinases (MMPs) are possibly involved in cardiac remodeling. However, the relationship between IL-18 signaling, cardiac hypertrophy, and the molecular mechanisms involved remain to be fully elucidated.
To elucidate the relationship between HTR2B and IL-18-induced myocardial hypertrophy and examine the antihypertrophic effects of EGCG and PPARδ.
We induced H9c2 cardiomyoblast hypertrophy with IL-18 in vitro and investigated the downstream signaling by real-time polymerase chain reaction (PCR) and western blotting. Hypertrophy was assessed by flow cytometry. We determined the effects of EGCG and PPARδ on IL-18-induced hypertrophic signaling via HTR2B-dependent mechanisms.
IL-18-induced H9c2 hypertrophy upregulated brain natriuretic peptide (BNP) protein and mRNA expression by inducing the expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and the hypertrophy was attenuated by pretreatment with EGCG (20 μM) and L-165,041 (2 μM), a PPARδ agonist. IL-18 upregulated the expression of HTR2B, which was inhibited by pretreatment with EGCG and L-165,041. SB215505 (0.1 μM), a HTR2B antagonist and siRNA for HTR2B, attenuated H9c2 hypertrophy significantly. Inhibition of HTR2B also downregulated the expression of MMP-3 and MMP-9.
IL-18 and HTR2B play critical roles in cardiomyoblast hypertrophy. EGCG and L-165,041 inhibit the expression of HTR2B and augment remodeling of H9c2 cardiomyoblasts, possibly mediated by MMP-3 and MMP-9.
在心力衰竭患者中，循环系统和受损心肌组织中的白细胞介素 - 18（IL - 18）水平会升高。血清素（5 - 羟色胺）受体2B亚型（HTR2B）在心脏功能和发育中起重要作用，其在大鼠中的过表达会导致心肌肥大。表没食子儿茶素没食子酸酯（EGCG）对大鼠心肌缺血 - 再灌注损伤具有心脏保护作用，并且在体内可预防压力超负荷介导的心脏肥大。过氧化物酶体增殖物激活受体δ（PPARδ）缺陷的小鼠可能会出现心脏功能障碍、心肌肥大和心力衰竭。基质金属蛋白酶（MMPs）可能参与心脏重塑。然而，IL - 18信号传导、心脏肥大之间的关系以及涉及的分子机制仍有待充分阐明。
阐明HTR2B与IL - 18诱导的心肌肥大之间的关系，并研究EGCG和PPARδ的抗肥大作用。
我们在体外用IL - 18诱导H9c2心肌成纤维细胞肥大，并通过实时聚合酶链反应（PCR）和蛋白质印迹法研究下游信号传导。通过流式细胞术评估肥大情况。我们通过HTR2B依赖性机制确定了EGCG和PPARδ对IL - 18诱导的肥大信号传导的影响。
IL - 18诱导的H9c2肥大通过诱导活化B细胞核因子κB轻链增强子（NF - κB）的表达上调脑钠肽（BNP）蛋白和mRNA表达，并且用EGCG（20μM）和PPARδ激动剂L - 165,041（2μM）预处理可减轻肥大。IL - 18上调HTR2B的表达，而用EGCG和L - 165,041预处理可抑制该表达。HTR2B拮抗剂SB215505（0.1μM）和HTR2B的小干扰RNA（siRNA）可显著减轻H9c2肥大。抑制HTR2B也会下调MMP - 3和MMP - 9的表达。
IL - 18和HTR2B在心肌成纤维细胞肥大中起关键作用。EGCG和L - 165,041抑制HTR2B的表达并增强H9c2心肌成纤维细胞的重塑，这可能由MMP - 3和MMP - 9介导。
