Inhibition of prolyl hydroxylases alters cell metabolism and reverses pre-existing diastolic dysfunction in mice.
Inhibition of prolyl hydroxylases alters cell metabolism and reverses pre-existing diastolic dysfunction in mice.
复制标题
DOI：
10.1016/j.ijcard.2018.08.065
复制
发表时间：
2018-12-01
影响因子：
3.5
通讯作者：
Chen JX
中科院分区：
文献类型：
--
作者：
He X;Zeng H;Roman RJ;Chen JX
舒张功能障碍正在成为老年人群心力衰竭的主要原因。诱导缺氧耐受性和重编程细胞代谢已成为治疗心血管疾病的新治疗策略。在本研究中，我们发现sirtuin 3 （SIRT3）的缺失导致舒张功能障碍，同时脯氨酰羟化酶（PHD） 1和2的表达显著增加。我们进一步研究了PHD在舒张功能障碍发展中的作用，给12-14月龄小鼠服用PHD抑制剂二甲基氧基酰甘氨酸（DMOG） 2周。DMOG可提高冠状动脉内皮缺氧诱导因子(HIF)-1α的表达。这伴随着冠状动脉血流储备和舒张功能的显著改善。抑制PHD通过增加糖酵解和减少氧消耗改变内皮代谢。最重要的是，DMOG治疗完全逆转了内皮特异性SIRT3缺陷小鼠先前存在的舒张功能障碍。我们的研究结果表明，抑制PHD和重编程细胞代谢可以逆转SIRT3缺陷小鼠先前存在的舒张功能障碍。我们的研究为与冠状动脉微血管功能障碍相关的舒张功能障碍患者，特别是SIRT3降低的老年人群，提供了诱导缺氧耐受性的潜在治疗策略。
Diastolic dysfunction is emerging as a leading cause of heart failure in aging population. Induction of hypoxia tolerance and reprogrammed cell metabolism have emerged as novel therapeutic strategies for the treatment of cardiovascular diseases. In the present study, we showed that deletion of sirtuin 3 (SIRT3) resulted in a diastolic dysfunction together with a significant increase in the expression of prolyl hydroxylases (PHD) 1 and 2. We further investigated the involvement of PHD in the development of diastolic dysfunction by treating the 12–14 months old mice with a PHD inhibitor, dimethyloxalylglycine (DMOG) for 2 weeks. DMOG treatment increased the expression of hypoxia-inducible factor (HIF)-1α in the endothelium of coronary arteries. This was accompanied by a significant improvement of coronary flow reserve and diastolic function. Inhibition of PHD altered endothelial metabolism by increasing glycolysis and reducing oxygen consumption. Most importantly, treatment with DMOG completely reversed the pre-existing diastolic dysfunction in the endothelial-specific SIRT3 deficient mice. Our findings demonstrate that inhibition of PHD and reprogrammed cell metabolism can reverse the pre-existed diastolic dysfunction in SIRT3 deficient mice. Our study provides a potential therapeutic strategy of induction of hypoxia tolerance for patients with diastolic dysfunction associated with coronary microvascular dysfunction, especially in the aging population with reduced SIRT3.
登录
查看更多内容
影响因子：
16
作者：
Hirschey MD;Shimazu T;Jing E;Grueter CA;Collins AM;Aouizerat B;Stančáková A;Goetzman E;Lam MM;Schwer B;Stevens RD;Muehlbauer MJ;Kakar S;Bass NM;Kuusisto J;Laakso M;Alt FW;Newgard CB;Farese RV Jr;Kahn CR;Verdin E
通讯作者：
Verdin E
影响因子：
8
作者：
Gonzalez-Flores, A.;Aguilar-Quesada, R.;Oliver, F. J.
通讯作者：
Oliver, F. J.
影响因子：
3.3
作者：
Favier, Francois B.;Britto, Florian A.;Py, Guillaume
通讯作者：
Py, Guillaume
影响因子：
20.1
作者：
FOREMAN, B;DAI, XZ;BACHE, RJ
通讯作者：
BACHE, RJ
影响因子：
24
作者：
Hogg, K;Swedberg, K;McMurray, J
通讯作者：
McMurray, J