Conning-Rowland Marcella S, Giannoudi Marilena, Drozd Michael, Brown Oliver I, Yuldasheva Nadira Y, Cheng Chew W, Meakin Paul J, Straw Sam, Gierula John, Ajjan Ramzi A, Kearney Mark T, Levelt Eylem, Roberts Lee D, Griffin Kathryn J, Cubbon Richard M
LIGHT Laboratories, Leeds Institute of Cardiovascular and Metabolic Medicine, The University of Leeds, Leeds, UK.
Cardiovasc Res. 2024 Dec 4;120(15):1898-1906. doi: 10.1093/cvr/cvae181.
Diabetes mellitus (DM) increases heart failure incidence and worsens prognosis, but its molecular basis is poorly defined in humans. We aimed to define the diabetic myocardial transcriptome and validate hits in their circulating protein form to define disease mechanisms and biomarkers.
RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project was used to define differentially expressed genes (DEGs) in right atrial (RA) and left ventricular (LV) myocardium from people with vs. without DM (type 1 or 2). DEGs were validated as plasma proteins in the UK Biobank cohort, searching for directionally concordant differential expression. Validated plasma proteins were characterized in UK Biobank participants, irrespective of diabetes status, using cardiac magnetic resonance imaging, incident heart failure, and cardiovascular mortality. We found 32 and 32 DEGs associated with DM in the RA and LV, respectively, with no overlap between these. Plasma proteomic data were available for 12, with ERBB3, NRXN3, and HSPA2 (all LV hits) exhibiting directional concordance. Irrespective of DM status, lower circulating ERBB3 and higher HSPA2 were associated with impaired LV contractility and higher LV mass. Participants in the lowest quartile of circulating ERBB3 or highest quartile of circulating HSPA2 had increased incident heart failure and cardiovascular death vs. all other quartiles.
DM is characterized by lower Erbb3 and higher Hspa2 expression in the myocardium, with directionally concordant differences in their plasma protein concentration. These are associated with LV dysfunction, incident heart failure, and cardiovascular mortality.
糖尿病（DM）会增加心力衰竭的发病率并恶化预后，但其在人类中的分子基础尚不清楚。我们旨在确定糖尿病心肌转录组，并验证其循环蛋白形式的命中靶点，以确定疾病机制和生物标志物。
利用基因型-组织表达（GTEx）项目的RNA测序数据，确定1型或2型糖尿病患者与非糖尿病患者右心房（RA）和左心室（LV）心肌中差异表达基因（DEG）。在英国生物银行队列中，将DEG作为血浆蛋白进行验证，寻找方向一致的差异表达。在英国生物银行参与者中，无论糖尿病状态如何，使用心脏磁共振成像、新发心力衰竭和心血管死亡率对验证后的血浆蛋白进行特征分析。我们分别在RA和LV中发现了32个与DM相关的DEG，两者之间没有重叠。有12个血浆蛋白质组学数据可用，其中ERBB3、NRXN3和HSPA2（均为LV命中靶点）表现出方向一致性。无论DM状态如何，循环中较低的ERBB3和较高的HSPA2与LV收缩功能受损和较高的LV质量相关。循环中ERBB3处于最低四分位数或HSPA2处于最高四分位数的参与者与所有其他四分位数相比，新发心力衰竭和心血管死亡增加。
DM的特征是心肌中Erbb3表达较低，Hspa2表达较高，其血浆蛋白浓度存在方向一致的差异。这些与LV功能障碍、新发心力衰竭和心血管死亡率相关。
