McLendon Patrick M, Ferguson Bradley S, Osinska Hanna, Bhuiyan Md Shenuarin, James Jeanne, McKinsey Timothy A, Robbins Jeffrey
The Heart Institute, Department of Pediatrics, Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; and.
Department of Medicine, Division of Cardiology, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO 80045.
Proc Natl Acad Sci U S A. 2014 Dec 2;111(48):E5178-86. doi: 10.1073/pnas.1415589111. Epub 2014 Nov 17.
Proteinopathy causes cardiac disease, remodeling, and heart failure but the pathological mechanisms remain obscure. Mutated αB-crystallin (CryAB(R120G)), when expressed only in cardiomyocytes in transgenic (TG) mice, causes desmin-related cardiomyopathy, a protein conformational disorder. The disease is characterized by the accumulation of toxic misfolded protein species that present as perinuclear aggregates known as aggresomes. Previously, we have used the CryAB(R120G) model to determine the underlying processes that result in these pathologic accumulations and to explore potential therapeutic windows that might be used to decrease proteotoxicity. We noted that total ventricular protein is hypoacetylated while hyperacetylation of α-tubulin, a substrate of histone deacetylase 6 (HDAC6) occurs. HDAC6 has critical roles in protein trafficking and autophagy, but its function in the heart is obscure. Here, we test the hypothesis that tubulin acetylation is an adaptive process in cardiomyocytes. By modulating HDAC6 levels and/or activity genetically and pharmacologically, we determined the effects of tubulin acetylation on aggregate formation in CryAB(R120G) cardiomyocytes. Increasing HDAC6 accelerated aggregate formation, whereas siRNA-mediated knockdown or pharmacological inhibition ameliorated the process. HDAC inhibition in vivo induced tubulin hyperacetylation in CryAB(R120G) TG hearts, which prevented aggregate formation and significantly improved cardiac function. HDAC6 inhibition also increased autophagic flux in cardiomyocytes, and increased autophagy in the diseased heart correlated with increased tubulin acetylation, suggesting that autophagy induction might underlie the observed cardioprotection. Taken together, our data suggest a mechanistic link between tubulin hyperacetylation and autophagy induction and points to HDAC6 as a viable therapeutic target in cardiovascular disease.
蛋白病可导致心脏疾病、心脏重塑和心力衰竭，但其病理机制仍不清楚。突变的αB-晶状体蛋白（CryAB(R120G)）仅在转基因（TG）小鼠的心肌细胞中表达时，会导致结蛋白相关的心肌病，这是一种蛋白质构象紊乱疾病。该疾病的特征是有毒的错误折叠蛋白物种积累，表现为核周聚集体，即称为聚集体的结构。此前，我们已使用CryAB(R120G)模型来确定导致这些病理积累的潜在过程，并探索可能用于降低蛋白毒性的潜在治疗窗口期。我们注意到心室总蛋白乙酰化不足，而组蛋白脱乙酰酶6（HDAC6）的底物α-微管蛋白发生了过度乙酰化。HDAC6在蛋白质运输和自噬中起关键作用，但其在心脏中的功能尚不清楚。在此，我们测试微管蛋白乙酰化是心肌细胞中的一种适应性过程这一假设。通过基因和药理学方法调节HDAC6水平和/或活性，我们确定了微管蛋白乙酰化对CryAB(R120G)心肌细胞中聚集体形成的影响。增加HDAC6会加速聚集体形成，而小干扰RNA介导的敲低或药理学抑制则改善了这一过程。体内HDAC抑制在CryAB(R120G) TG心脏中诱导微管蛋白过度乙酰化，这阻止了聚集体形成并显著改善了心脏功能。HDAC6抑制还增加了心肌细胞中的自噬通量，患病心脏中自噬增加与微管蛋白乙酰化增加相关，这表明自噬诱导可能是观察到的心脏保护作用的基础。综上所述，我们的数据表明微管蛋白过度乙酰化与自噬诱导之间存在机制联系，并指出HDAC6是心血管疾病中一个可行的治疗靶点。
