人类心脏病中胃饥饿素-生长激素促分泌素受体信号系统的区域差异
Regional Differences in the Ghrelin-Growth Hormone Secretagogue Receptor Signalling System in Human Heart Disease.
作者信息
Sullivan Rebecca, Randhawa Varinder K, Lalonde Tyler, Yu Tina, Kiaii Bob, Luyt Leonard, Wisenberg Gerald, Dhanvantari Savita
机构信息
Pathology and Laboratory Medicine, Western University, London, Ontario, Canada.
Cardiology Division, Toronto General Hospital, University Health Network, and University of Toronto, Ontario, Canada.
出版信息
CJC Open. 2020 Nov 4;3(2):182-194. doi: 10.1016/j.cjco.2020.10.015. eCollection 2021 Feb.
BACKGROUND
The hormone ghrelin and its receptor, the growth hormone secretagogue receptor (GHSR) are expressed in myocardium. GHSR binding activates signalling pathways coupled to cardiomyocyte survival and contractility. These properties have made the ghrelin-GHSR axis a candidate for a biomarker of cardiac function. The dynamics of ghrelin-GHSR are altered significantly in late stages of heart failure (HF) and cardiomyopathy, when left ventricular (LV) function is failing. We examined the relationship of GHSR with ghrelin in cardiac tissue from patients with valvular disease with no detectable changes in LV function.
METHODS
Biopsy samples from the left ventricle and left atrium were obtained from 25 patients with valvular disease (of whom 13 also had coronary artery disease) and preserved LV ejection fraction, and compared to control samples obtained via autopsy. Using quantitative confocal fluorescence microscopy, levels of GHSR were determined using [Dpr(n-octanoyl),Lys(sulfo-Cy5)]ghrelin(1-19), and immunofluorescence determined ghrelin, the heart failure marker natriuretic peptide type-B (BNP), and contractility marker sarcoplasmic reticulum ATPase pump (SERCA2a).
RESULTS
A positive correlation between GHSR and ghrelin was apparent in only diseased tissue. Ghrelin and BNP significantly correlated in the left ventricle and strongly colocalized to the same intracellular compartment in diseased and control tissue. GHSR, ghrelin, and BNP all strongly and significantly correlated with SERCA2a in the left ventricle of diseased tissue only.
CONCLUSIONS
Our results suggest that the dynamics of the myocardial ghrelin-GHSR axis is altered in cardiovascular disease in the absence of measurable changes in heart function, and might accompany a regional shift in endocrine programming.
背景
激素胃饥饿素及其受体，即生长激素促分泌素受体（GHSR），在心肌中表达。GHSR结合激活与心肌细胞存活和收缩性相关的信号通路。这些特性使胃饥饿素 - GHSR轴成为心脏功能生物标志物的候选者。在心力衰竭（HF）和心肌病的晚期，当左心室（LV）功能衰竭时，胃饥饿素 - GHSR的动态变化会显著改变。我们研究了瓣膜病患者心脏组织中GHSR与胃饥饿素的关系，这些患者的左心室功能无明显变化。
方法
从25例瓣膜病患者（其中13例也患有冠状动脉疾病）获取左心室和左心房的活检样本，其左心室射血分数得以保留，并与通过尸检获得的对照样本进行比较。使用定量共聚焦荧光显微镜，通过[Dpr（正辛酰基），Lys（磺基 - Cy5）]胃饥饿素（1 - 19）测定GHSR水平，并通过免疫荧光测定胃饥饿素、心力衰竭标志物B型利钠肽（BNP）和收缩性标志物肌浆网ATP酶泵（SERCA2a）。
结果
仅在病变组织中，GHSR与胃饥饿素之间存在明显的正相关。胃饥饿素与BNP在左心室中显著相关，并且在病变和对照组织中强烈共定位于同一细胞内区室。仅在病变组织的左心室中，GHSR、胃饥饿素和BNP均与SERCA2a强烈且显著相关。
结论
我们的结果表明，在心脏功能无明显可测变化的心血管疾病中，心肌胃饥饿素 - GHSR轴的动态变化会改变，并且可能伴随着内分泌编程的区域转移。
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