L-Carnitine prevents the development of ventricular fibrosis and heart failure with preserved ejection fraction in hypertensive heart disease

被引：82

作者：

Omori, Yosuke ^{[2
,3
]}

Ohtani, Tomohito ^{[2
,3
]}

Sakata, Yasushi ^{[2
]}

Mano, Toshiaki ^{[2
,3
]}

Takeda, Yasuharu ^{[2
,3
]}

Tamaki, Shunsuke ^{[2
,3
]}

Tsukamoto, Yasumasa ^{[2
,3
]}

Kamimura, Daisuke ^{[2
,3
]}

Aizawa, Yoshihiro ^{[2
]}

Miwa, Takeshi ^{[3
]}

Komuro, Issei ^{[2
]}

Soga, Tomoyoshi ^{[4
]}

Yamamoto, Kazuhiro ^{[1
]}

机构：

[1] Tottori Univ, Dept Mol Med & Therapeut, Fac Med, Yonago, Tottori 6838503, Japan

[2] Osaka Univ, Dept Cardiovasc Med, Grad Sch Med, Suita, Osaka, Japan

[3] Osaka Univ, Genome Informat Res Ctr, Suita, Osaka, Japan

[4] Keio Univ, Inst Adv Biosci, Tsuruoka, Yamagata, Japan

来源：

JOURNAL OF HYPERTENSION | 2012年 / 30卷 / 09期

关键词：

carnitine; diastolic heart failure; fibrosis; prostacyclin; CARDIAC-HYPERTROPHY; MASS-SPECTROMETRY; RECEPTOR BLOCKER; OXIDATIVE STRESS; ADVANCED-STAGE; RATS; CARDIOMYOPATHY; METABOLOMICS; PROSTACYCLIN; PREVALENCE;

D O I：

10.1097/HJH.0b013e3283569c5a

中图分类号：

R6 [外科学];

学科分类号：

100210 [外科学];

摘要：

Objectives: Prognosis of heart failure with preserved ejection fraction (HFpEF) remains poor because of unknown pathophysiology and unestablished therapeutic strategy. This study aimed to identify a potential therapeutic intervention for HFpEF through metabolomics-based analysis. Methods and results: Metabolomics with capillary electrophoresis time-of-flight mass spectrometry was performed using plasma of Dahl salt-sensitive rats fed high-salt diet, a model of hypertensive HFpEF, and showed decreased free-carnitine levels. Reassessment with enzymatic cycling method revealed the decreased plasma and left-ventricular free-carnitine levels in the HFpEF model. Urinary free-carnitine excretion was increased, and the expression of organic cation/carnitine transporter 2, which transports free-carnitine into cells, was down-regulated in the left ventricle (LV) and kidney in the HFpEF model. L-Carnitine was administered to the hypertensive HFpEF model. L-Carnitine treatment restored left-ventricular free-carnitine levels, attenuated left-ventricular fibrosis and stiffening, prevented pulmonary congestion, and improved survival in the HFpEF model independent of the antihypertensive effects, accompanied with increased expression of fatty acid desaturase (FADS) 1/2, rate-limiting enzymes in forming arachidonic acid, and enhanced production of arachidonic acid, a precursor of prostacyclin, and prostacyclin in the LV. In cultured cardiac fibroblasts, L-carnitine attenuated the angiotensin II-induced collagen production with increased FADS1/2 expression and enhanced production of arachidonic acid and prostacyclin. L-Carnitine-induced increase of arachidonic acid was canceled by knock-down of FADS1 or FADS2 in cultured cardiac fibroblasts. Serum free-carnitine levels were decreased in HFpEF patients. Conclusions: L-carnitine supplementation attenuates cardiac fibrosis by increasing prostacyclin production through arachidonic acid pathway, and may be a promising therapeutic option for HFpEF.

引用

页码：1834 / 1844

页数：11

共 56 条

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