Significance of ventricular myocytes and nonmyocytes interaction during cardiocyte hypertrophy: evidence for endothelin-1 as a paracrine hypertrophic factor from cardiac nonmyocytes.
BACKGROUND
In cardiac hypertrophy, both excessive enlargement of cardiac myocytes and progressive interstitial fibrosis are well known to occur simultaneously. In the present study, to investigate the interaction between ventricular myocytes (MCs) and cardiac nonmyocytes (NMCs), mostly fibroblasts, during cardiocytes hypertrophy, we examined the change in cell size and gene expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in cultured MCs as markers for hypertrophy in the neonatal rat ventricular cardiac cell culture system.


RESULTS
The size of cultured MCs significantly increased in the MC-NMC coculture. Concomitantly, secretions of ANP and BNP into culture media were significantly increased in the MC-NMC coculture compared with in the MC culture (with the possible contamination of NMC <1% of MC). Moreover, in the MC culture, enlargement of MC and an increase in ANP and BNP secretions were induced by treatment with conditioned media of the NMC culture. A considerable amount of endothelin (ET)-1 production was detected in the NMC-conditioned media. BQ-123, an ET-A receptor antagonist, and bosentan, a nonselective ET receptor antagonist, significantly blocked the hypertrophic response of MCs induced by treatment with NMC-conditioned media. Angiotensin II (Ang II) (10(-10) to 10(-6) mol/L) and transforming growth factor-beta1 (TGF-beta1) (10(-13) to 10(-9) mol/L), both of which are known to be cardiac hypertrophic factors, did not induce hypertrophy in MC culture, but both Ang II and TGF-beta1 increased the size of MCs and augmented ANP and BNP productions in the MC-NMC coculture. This hypertrophic activity of Ang II and TGF-beta1 was associated with the potentiation of ET-1 production in the MC-NMC coculture, and the effect of Ang II or TGF-beta1 on the secretions of ANP and BNP in the coculture was significantly suppressed by pretreatment with BQ-123.


CONCLUSIONS
These results demonstrate that NMCs regulate MC hypertrophy at least partially via ET-1 secretion and that the interaction between MCs and NMCs plays a critical role during the process of Ang II- or TGF-beta1-induced cardiocyte hypertrophy.
Harada
M
M
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Japan.
Itoh
H
H
Nakagawa
O
O
Ogawa
Y
Y
Miyamoto
Y
Y
Kuwahara
K
K
Ogawa
E
E
Igaki
T
T
Yamashita
J
J
Masuda
I
I
Yoshimasa
T
T
Tanaka
I
I
Saito
Y
Y
Nakao
K
K
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D006332:Cardiomegaly / Q000473:pathology* / Q000503:physiopathology*; D002417:Cattle; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology*; D006984:Hypertrophy; D008077:Lipoproteins, LDL / Q000378:metabolism; D009206:Myocardium / Q000473:pathology*; D020097:Natriuretic Peptide, Brain; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019899:Paracrine Communication / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011945:Receptors, Angiotensin / Q000235:genetics; D017466:Receptors, Endothelin / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D016276:Ventricular Function / Q000502:physiology*
D017077:Culture Media, Conditioned; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D008077:Lipoproteins, LDL; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D011945:Receptors, Angiotensin; D017466:Receptors, Endothelin; D016212:Transforming Growth Factor beta; C032629:acetyl-LDL; D000804:Angiotensin II; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor