Effects of olmesartan, an angiotensin II receptor blocker, on mechanically-modulated genes in cardiac myocytes.
BACKGROUND
Angiotensin II plays an important role in cardiac hypertrophy or remodeling. Angiotensin II receptor blockers (ARB) are clinically useful for the treatment of hypertension and heart failure. However, the molecular effects of ARB in the mechanically-stressed myocardium have not been completely defined. We investigated the effects of ARB on mechanically-modulated genes in cardiac myocytes.


METHODS
We used powerful DNA microarray technology to study the effects of the ARB, CS-886 (olmesartan), on genes modulated in neonatal rat cardiac myocytes using mechanical stimuli. Mechanical deformation was applied to a thin and transparent membrane on which neonatal rat cardiac myocytes were cultured in the presence or absence of RNH-6270, an active metabolite of CS-886. Expression profiles of 8000 rat genes using the Affymetrix GeneChip (Rat Genome U34A) were investigated with mRNA obtained from the samples above.


RESULTS
Nine genes induced under 4% mechanical strain were significantly suppressed by RNH-6270 in rat cardiac myocytes: monoamine oxidase B, neuromedine B receptor, olfactory receptor, synaptotagmin XI, retinol-binding protein, and 4 expressed sequence tags (ESTs). In contrast, 21 genes suppressed under mechanical strain were significantly restored by RNH-6270: major acute phase alpha 1-protein, Sp-1, Bcl-Xalpha, JAK2, 2 genes encoding detoxification, few genes for receptor, structure, metabolism or ion channel, and 10 ESTs.


CONCLUSIONS
As some of these genes may be involved in promoting or modulating cardiac remodeling, these findings suggest that ARB may affect cardiovascular morbidity and mortality partially via these molecular alterations.
Division of Cardiovascular Medicine, Jichi Medical School, Minamikawachi-Machi, Tochigi, Japan 329-0498.
Ruri
R
Ohki
Keiji
K
Yamamoto
Shuichi
S
Ueno
Hiroyuki
H
Mano
Uichi
U
Ikeda
Kazuyuki
K
Shimada
D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D000068557:Olmesartan Medoxomil; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013314:Stress, Mechanical; D013777:Tetrazoles / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000068557:Olmesartan Medoxomil; C437965:olmesartan