Department of Cell and Molecular Physiology, Loyola University Stritch School of Medicine, Maywood, Illinois.
Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, Ohio.
Am J Physiol Heart Circ Physiol. 2021 Jun 1;320(6):H2339-H2350. doi: 10.1152/ajpheart.00419.2020. Epub 2021 May 14.
Mutations to the sarcomere-localized cochaperone protein Bcl2-associated athanogene 3 (BAG3) are associated with dilated cardiomyopathy (DCM) and display greater penetrance in male patients. Decreased protein expression of BAG3 is also associated with nongenetic heart failure; however, the factors regulating cardiac BAG3 expression are unknown. Using left ventricular (LV) tissue from nonfailing and DCM human samples, we found that whole LV BAG3 expression was not significantly impacted by DCM or sex; however, myofilament localized BAG3 was significantly decreased in males with DCM. Females with DCM displayed no changes in BAG3 compared with nonfailing. This sex difference appears to be estrogen independent, as estrogen treatment in ovariectomized female rats had no impact on BAG3 expression. BAG3 gene expression in noncardiac cells is primarily regulated by the heat shock transcription factor-1 (HSF-1). We show whole LV HSF-1 expression and nuclear localized/active HSF-1 each displayed a striking positive correlation with whole LV BAG3 expression. We further found that HSF-1 localizes to the sarcomere -disc in cardiomyocytes and that this myofilament-associated HSF-1 pool decreases in heart failure. The decrease of HSF-1 was more pronounced in male patients and tightly correlated with myofilament BAG3 expression. Together our findings indicate that cardiac BAG3 expression and myofilament localization are differentially impacted by sex and disease and are linked to HSF-1. Myofilament BAG3 expression decreases in male patients with nonischemic DCM but is preserved in female patients with DCM. BAG3 expression in the human heart is tightly linked to HSF-1 expression and nuclear translocation. HSF-1 localizes to the sarcomere Z-disc in the human heart. HSF-1 expression in the myofilament fraction decreases in male patients with DCM and positively correlates with myofilament BAG3.
肌节局部共伴侣蛋白 Bcl2 相关抗凋亡基因 3（BAG3）的突变与扩张型心肌病（DCM）有关，并且在男性患者中具有更高的外显率。BAG3 蛋白表达降低也与非遗传性心力衰竭有关；然而，调节心脏 BAG3 表达的因素尚不清楚。使用来自非衰竭和 DCM 人类样本的左心室（LV）组织，我们发现 DCM 或性别并未显著影响整个 LV BAG3 的表达；然而，DCM 男性的肌丝定位 BAG3 显著减少。与非衰竭相比，DCM 女性的 BAG3 没有变化。这种性别差异似乎与雌激素无关，因为卵巢切除大鼠的雌激素治疗对 BAG3 表达没有影响。非心肌细胞中 BAG3 基因表达主要受热休克转录因子-1（HSF-1）调节。我们显示整个 LV HSF-1 表达和核定位/活性 HSF-1 与整个 LV BAG3 表达均呈显著正相关。我们进一步发现 HSF-1 定位于肌节 - 肌节在心肌细胞中，该肌节相关 HSF-1 池在心力衰竭时减少。HSF-1 的减少在男性患者中更为明显，与肌丝 BAG3 表达紧密相关。我们的研究结果表明，心脏 BAG3 表达和肌丝定位受性别和疾病的不同影响，并与 HSF-1 相关。非缺血性 DCM 男性患者的肌丝 BAG3 表达减少，但 DCM 女性患者的表达得到保留。人类心脏中的 BAG3 表达与 HSF-1 表达和核转位紧密相关。HSF-1 在人类心脏中定位于肌节 Z 盘。DCM 男性患者的肌丝部分 HSF-1 表达减少，并与肌丝 BAG3 呈正相关。
