Aliskiren affects fatty-acid uptake and lipid-related genes in rodent and human cardiomyocytes

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• 作者：Diego Rodr&#xed ; guez-Penas^a ; ¹ ; Sandra Feijó ; o-Band&#xed ; n^a ; ¹ ; Pamela V. Lear^a ; ¹ ; Ana Mosquera-Leal^a ; Vanessa Garc&#xed ; a-Rú ; a^a ; Manuel F. Otero^a ; Miguel Rivera^b ; Oreste Gualillo^c ; Jos&#xe9 ; Ramó ; n Gonz&#xe1 ; lez-Juanatey^a ; Francisca Lago^a ; ^{Francisca.Lago.Paz@sergas.es" rel="nofollow}
• 关键词：Cardiomyocytes ; Aliskiren ; Metabolism ; Lipids ; Cholesterol ; Glucose
• 刊名：Biochemical Pharmacology
• 出版年：2011
• 出版时间：1 September 2011
• 年：2011
• 卷：82
• 期：5
• 页码：491-504
• 全文大小：2052 K
• ISSN：S0006295211003340

文摘

Purpose

We investigated whether the direct renin inhibitor aliskiren can affect metabolism in cardiomyocytes from rat, mouse and human sources.

Methods and results

At 10–50 μmol/L, aliskiren significantly increased medium-chain-fatty-acid uptake in primary-cultured neonatal-rat and HL-1 adult-mouse-derived cardiomyocytes (BODIPY-induced fluorescence intensity). The fatty-acid transporter CD-36 was correspondingly translocated to, but the glucose transporter Glut-4 away from, the sarcoplasmic reticulum/plasma membrane, in primary-cultured neonatal-rat (CD-36, Glut-4) and adult-human (CD-36) cardiomyocytes (confocal immunocytochemistry). Immunoblotting showed that aliskiren induced phosphorylation of ERK1/2 in cardiomyocytes from all three sources; responses were dose- and time-dependent, unaffected by renin treatment, and did not cause alterations in expression of (P)R or Igf2/M6P receptors. Microarray analysis of the complete genome of aliskiren-treated neonatal-rat cardiomyocytes, with RT-qPCR and immunoblot confirmation assays in rat and human primary cardiomyocytes, showed that aliskiren up-regulated mRNA and increased protein expression of several enzymes important in lipid and glucose metabolism and in cholesterol biosynthesis. Cardiomyocyte cell-cycle and viability were unaffected by aliskiren.

Conclusions

Aliskiren can induce changes in fatty-acid and glucose uptake and expression of key enzymes of lipid and cholesterol metabolism, which are not associated with increased expression of (P)R or Igf2/M6P receptors, in cultured cardiomyocytes.