Division of Medicine, Akershus University Hospital, Lørenskog, Norway.
PLoS One. 2012;7(5):e37401. doi: 10.1371/journal.pone.0037401. Epub 2012 May 24.
Several beneficial effects have been demonstrated for secretogranin II (SgII) in non-cardiac tissue. As cardiac production of chromogranin A and B, two related proteins, is increased in heart failure (HF), we hypothesized that SgII could play a role in cardiovascular pathophysiology.
METHODOLOGY/PRINCIPAL FINDINGS: SgII production was characterized in a post-myocardial infarction heart failure (HF) mouse model, functional properties explored in experimental models, and circulating levels measured in mice and patients with stable HF of moderate severity. SgII mRNA levels were 10.5 fold upregulated in the left ventricle (LV) of animals with myocardial infarction and HF (p<0.001 vs. sham-operated animals). SgII protein levels were also increased in the LV, but not in other organs investigated. SgII was produced in several cell types in the myocardium and cardiomyocyte synthesis of SgII was potently induced by transforming growth factor-β and norepinephrine stimulation in vitro. Processing of SgII to shorter peptides was enhanced in the failing myocardium due to increased levels of the proteases PC1/3 and PC2 and circulating SgII levels were increased in mice with HF. Examining a pathophysiological role of SgII in the initial phase of post-infarction HF, the SgII fragment secretoneurin reduced myocardial ischemia-reperfusion injury and cardiomyocyte apoptosis by 30% and rapidly increased cardiomyocyte Erk1/2 and Stat3 phosphorylation. SgII levels were also higher in patients with stable, chronic HF compared to age- and gender-matched control subjects: median 0.16 (Q1-3 0.14-0.18) vs. 0.12 (0.10-0.14) nmol/L, p<0.001.
We demonstrate increased myocardial SgII production and processing in the LV in animals with myocardial infarction and HF, which could be beneficial as the SgII fragment secretoneurin protects from ischemia-reperfusion injury and cardiomyocyte apoptosis. Circulating SgII levels are also increased in patients with chronic, stable HF and may represent a new cardiac biomarker.
已证实脑肠肽 II（SgII）在非心脏组织中有多种有益作用。由于心力衰竭（HF）时心脏中嗜铬粒蛋白 A 和 B（两种相关蛋白）的产生增加，我们假设 SgII 可能在心血管病理生理学中发挥作用。
方法/主要发现：在心肌梗死后心力衰竭（HF）小鼠模型中对 SgII 产生进行了特征描述，在实验模型中探索了其功能特性，并在患有中度稳定 HF 的小鼠和患者中测量了循环水平。心肌梗死后和 HF 动物的左心室（LV）中 SgII mRNA 水平上调了 10.5 倍（p<0.001 与假手术动物相比）。LV 中的 SgII 蛋白水平也增加了，但其他研究的器官中没有增加。SgII 在心肌中的几种细胞类型中产生，体外转化生长因子-β和去甲肾上腺素刺激强烈诱导心肌细胞合成 SgII。由于蛋白酶 PC1/3 和 PC2 水平升高，SgII 的加工处理被增强，HF 小鼠的循环 SgII 水平升高。在心肌梗死后 HF 的初始阶段，SgII 片段分泌素可减少 30%的心肌缺血再灌注损伤和心肌细胞凋亡，并迅速增加心肌细胞 Erk1/2 和 Stat3 磷酸化。与年龄和性别匹配的对照组相比，患有稳定、慢性 HF 的患者的 SgII 水平也更高：中位数为 0.16（Q1-3：0.14-0.18）vs. 0.12（0.10-0.14）nmol/L，p<0.001。
我们在心肌梗死后和 HF 的动物的 LV 中发现心肌 SgII 产生和加工增加，这可能是有益的，因为 SgII 片段分泌素可防止缺血再灌注损伤和心肌细胞凋亡。患有慢性、稳定 HF 的患者的循环 SgII 水平也升高，可能代表一种新的心脏生物标志物。
