B-Type natriuretic peptide inhibited angiotensin II-stimulated cholesterol biosynthesis, cholesterol transfer, and steroidogenesis in primary human adrenocortical cells.
In this study, we demonstrate that B-type natriuretic peptide (BNP) opposed angiotensin II (Ang II)-stimulated de novo cholesterol biosynthesis, cellular cholesterol uptake, cholesterol transfer to the inner mitochondrial membrane, and steroidogenesis, which are required for biosynthesis of steroid hormones such as aldosterone and cortisol in primary human adrenocortical cells. BNP dose-dependently stimulated intracellular cGMP production with an EC(50) of 11 nm, implying that human adrenocortical cells express the guanylyl cyclase A receptor. cDNA microarray and real-time RT-PCR analyses revealed that BNP inhibited Ang II-stimulated genes related to cholesterol biosynthesis (acetoacetyl coenzyme A thiolase, HMG coenzyme A synthase 1, HMG coenzyme A reductase, isopentenyl-diphosphate Delta-isomerase, lanosterol synthase, sterol-4C-methyl oxidase, and emopamil binding protein/sterol isomerase), cholesterol uptake from circulating lipoproteins (scavenger receptor class B type I and low-density lipoprotein receptor), cholesterol transfer to the inner mitochondrial membrane (steroidogenic acute regulatory protein), and steroidogenesis (ferredoxin 1,3beta-hydroxysteroid dehydrogenase, glutathione transferase A3, CYP19A1, CYP11B1, and CYP11B2). Consistent with the microarray and real-time PCR results, BNP also blocked Ang II-induced binding of (125)I-labeled low-density lipoprotein and (125)I-labeled high-density lipoprotein to human adrenocortical cells. Furthermore, BNP markedly inhibited Ang II-stimulated release of estradiol, aldosterone, and cortisol from cultured primary human adrenocortical cells. These findings demonstrate that BNP opposes Ang II-induced steroidogenesis via multiple steps from cholesterol supply and transfer to the final formation of steroid hormones. This study provides new insights into the cellular mechanisms by which BNP modulates Ang II-induced steroidogenesis in the adrenal gland.
Liang
Faquan
F
Scios Inc., 6500 Paseo Padre Parkway, Fremont, California 94555, USA.
Kapoun
Ann M
AM
Lam
Andrew
A
Damm
Debby L
DL
Quan
Diana
D
O'Connell
Maile
M
Protter
Andrew A
AA
D000302:Adrenal Cortex / Q000166:cytology / Q000378:metabolism*; D000305:Adrenal Cortex Hormones / Q000096:biosynthesis; D000306:Adrenal Cortex Neoplasms; D018268:Adrenocortical Carcinoma; D000328:Adult; D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism; D004347:Drug Interactions; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000378:metabolism* / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis / Q000592:standards; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013256:Steroids / Q000096:biosynthesis; D014662:Vasoconstrictor Agents / Q000378:metabolism* / Q000494:pharmacology
D000305:Adrenal Cortex Hormones; D008074:Lipoproteins; D013256:Steroids; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D020097:Natriuretic Peptide, Brain; D002784:Cholesterol; D006152:Cyclic GMP