Histone deacetylase activity governs diastolic dysfunction through a nongenomic mechanism.
Histone deacetylase activity governs diastolic dysfunction through a nongenomic mechanism.
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DOI：
10.1126/scitranslmed.aao0144
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发表时间：
2018-02-07
影响因子：
17.1
通讯作者：
McKinsey TA
中科院分区：
文献类型：
--
作者：
Jeong MY;Lin YH;Wennersten SA;Demos-Davies KM;Cavasin MA;Mahaffey JH;Monzani V;Saripalli C;Mascagni P;Reece TB;Ambardekar AV;Granzier HL;Dinarello CA;McKinsey TA
没有批准的药物用于治疗射血分数保留性心力衰竭（HFpEF），其特征是左心室（LV）舒张功能障碍。我们证明了ITF2357（givinostat），一种临床阶段的组蛋白脱乙酰酶（HDAC）催化活性的抑制剂，在两种不同的舒张功能障碍与保留EF的小鼠模型中有效。ITF2357阻断了Dahl盐敏感性（DSS）大鼠中高血压引起的LV舒张功能障碍，并抑制了血压正常小鼠中衰老诱导的舒张功能障碍。HDAC介导的疗效不是由于降低血压或抑制通常与舒张功能障碍相关的细胞和分子事件，包括心脏纤维化、心脏肥大或心脏肌联蛋白和肌球蛋白亚型表达的变化。相反，离体研究显示心肌原纤维松弛受损是舒张功能障碍的一种先前未被认识到的肌细胞自主机制，可通过HDAC抑制来改善。将这些发现转化为人类，来自舒张功能障碍和保留EF的患者的心脏肌原纤维也表现出受损的松弛。这些数据表明，诸如HDAC抑制剂的药剂，其增强心脏肌原纤维松弛，有望用于治疗人类HFpEF。
There are no approved drugs for the treatment of heart failure with preserved ejection fraction (HFpEF), which is characterized by left ventricular (LV) diastolic dysfunction. We demonstrate that ITF2357 (givinostat), a clinical-stage inhibitor of histone deacetylase (HDAC) catalytic activity, is efficacious in two distinct murine models of diastolic dysfunction with preserved EF. ITF2357 blocked LV diastolic dysfunction due to hypertension in Dahl salt-sensitive (DSS) rats and suppressed aging-induced diastolic dysfunction in normotensive mice. HDAC inhibitor–mediated efficacy was not due to lowering blood pressure or inhibiting cellular and molecular events commonly associated with diastolic dysfunction, including cardiac fibrosis, cardiac hypertrophy, or changes in cardiac titin and myosin isoform expression. Instead, ex vivo studies revealed impairment of cardiac myofibril relaxation as a previously unrecognized, myocyte-autonomous mechanism for diastolic dysfunction, which can be ameliorated by HDAC inhibition. Translating these findings to humans, cardiac myofibrils from patients with diastolic dysfunction and preserved EF also exhibited compromised relaxation. These data suggest that agents such as HDAC inhibitors, which potentiate cardiac myofibril relaxation, hold promise for the treatment of HFpEF in humans.
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影响因子：
5.5
作者：
Fitzsimons, DP;Patel, JR;Moss, RL
通讯作者：
Moss, RL
影响因子：
8.3
作者：
Klotz, S;Hay, I;Burkhoff, D
通讯作者：
Burkhoff, D
影响因子：
4.8
作者：
Desai, Akshay S.;Lewis, Eldrin F.;Pfeffer, Marc A.
通讯作者：
Pfeffer, Marc A.
DOI：
10.1152/ajpheart.00967.2001
发表时间：
2004-03-01
影响因子：
4.8
作者：
Lamberts, RR;Willemsen, MJJMF;Westerhof, N
通讯作者：
Westerhof, N
影响因子：
9.7
作者：
Donaldson, Cameron;Palmer, Bradley M.;LeWinter, Martin M.
通讯作者：
LeWinter, Martin M.