Heart Failure With Preserved Ejection Fraction Induces Beiging in Adipose Tissue.
Heart Failure With Preserved Ejection Fraction Induces Beiging in Adipose Tissue.
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DOI：
10.1161/circheartfailure.115.002724
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发表时间：
2016-01
期刊：
影响因子：
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通讯作者：
Sam F
中科院分区：
文献类型：
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作者：
Valero-Muñoz M;Li S;Wilson RM;Hulsmans M;Aprahamian T;Fuster JJ;Nahrendorf M;Scherer PE;Sam F
尽管射血分数保留性心力衰竭（HFpEF）在人类中的患病率不断增加，但目前尚无针对HFpEF的循证疗法。临床研究表明，肥胖相关的功能失调性脂肪组织（AT）和HFpEF之间的关系。然而，在一些BMI较高的HF人群中存在明显的肥胖悖论。我们试图确定HFpEF是否对AT产生影响，并研究相关机制。小鼠接受d-醛固酮输注，单侧肾切除术，并给予1%生理盐水4周。HFpEF小鼠出现高血压、左心室肥厚、舒张功能障碍，心肌利钠肽表达增加。尽管HFpEF和假手术小鼠的体重相似，但HFpEF中的白色AT（WAT）显著小于假手术小鼠（附睾AT：7.59 vs. 10.67 mg/g;腹股沟AT：6.34 vs. 8.38 mg/g）。这些变化与WAT中较小的脂肪细胞大小和增加的beiging标志物（ucp-1，cidea和伊娃）有关。在TAC诱导的HFpEF中观察到类似的结果。在HFpEF小鼠的WAT中观察到利钠肽信号传导的活化增加。信号受体npra与清除受体nprc的比率增加，p38 MAPK活化也是如此。然而，HFpEF小鼠在低温暴露期间不能调节体温。在HFpEF中，尽管有较大的棕色AT质量（BAT; 5.96对4.50 mg/g），但BAT显示出活性降低，与假手术相比，ucp 1、cidea和伊娃表达降低，脂解酶（hsl、lpl和fabp 4）表达降低。这些发现表明HFpEF与WAT中的beiging和功能失调的BAT相关。
Despite the increasing prevalence of heart failure with preserved ejection fraction (HFpEF) in humans, there are no evidence-based therapies for HFpEF. Clinical studies suggest a relationship between obesity-associated dysfunctional adipose tissue (AT) and HFpEF. However an apparent obesity paradox exists in some HF populations with a higher BMI. We sought to determine if HFpEF exerted effects on AT and investigated the involved mechanisms. Mice underwent d-aldosterone infusion, uninephrectomy, and were given 1% saline for 4 weeks. HFpEF mice developed hypertension, left ventricular hypertrophy, diastolic dysfunction and had higher myocardial natriuretic peptide expression. Although body weights were similar in HFpEF and sham-operated mice, white AT (WAT) was significantly smaller in HFpEF than Sham (epididymal AT: 7.59 vs. 10.67 mg/g; inguinal AT: 6.34 vs. 8.38 mg/g). These changes were associated with smaller adipocyte size and increased beiging markers (ucp-1, cidea and eva) in WAT. Similar findings were seen in HFpEF induced by TAC. Increased activation of natriuretic peptide signaling was seen in WAT of HFpEF mice. The ratio of the signaling receptor, npra, to the clearance receptor, nprc, was increased as was p38 MAPK activation. However, HFpEF mice failed to regulate body temperature during cold temperature exposure. In HFpEF, despite a larger brown AT mass (BAT; 5.96 vs. 4.50 mg/g), BAT showed reduced activity with decreased ucp1, cidea and eva expression, and decreased expression of lipolytic enzymes (hsl, lpl and fabp4) vs. Sham. These findings show that HFpEF is associated with beiging in WAT and with dysfunctional BAT.