Cell proliferation in carcinoid valve disease: a mechanism for serotonin effects.
OBJECTIVE
Elevated serum serotonin is associated with carcinoid heart disease, the hallmark of which is valvular thickening. Yet, the mechanistic role of serotonin in carcinoid heart disease is poorly understood. We postulated that serotonin has a direct mitogenic effect on cardiac valvular subendocardial cells, and that this effect is mediated by serotonin receptors.


METHODS
The dose-dependent proliferative effects of serotonin (10(-8) to 10(-4)M) on cultured porcine aortic valve cells via a [3H]thymidine assay were determined in vitro. Serotonin receptor antagonist studies in culture were also performed using methiotepin, a 5HT1b antagonist, and ketanserin, a 5HT2 receptor antagonist, to determine the mechanism of serotonin action. The ex-vivo proliferation level in human carcinoid (n = 26) and normal valves (n = 10) was compared using proliferating cell nuclear antigen (PCNA) staining, a marker for proliferation. Identification and localization of specific 5HT receptor was assessed by immunostaining for serotonin receptors in the valves.


RESULTS
Serotonin increased valvular proliferation in vitro in a dose-dependent manner (10-fold increase) (p <0.001), and this mitogenic effect was inhibited by methiotepin but not ketanserin. In human carcinoid heart valves the level of proliferation was 35-fold higher than in normal human valves (p <0.001). 5HT1b receptors were found only in the carcinoid valves, and not in the normal valves.


CONCLUSIONS
Serotonin is a powerful mitogen for valvular subendocardial cells. The mitogenic effect is at least partly mediated via 5HT1b receptors. Subendothelial cell proliferation is significantly elevated in human carcinoid valves in vivo. The data suggest a mechanism whereby serotonin may contribute to valvular proliferation in carcinoid heart disease.
Rajamannan
N M
NM
Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA.
Caplice
N
N
Anthikad
F
F
Sebo
T J
TJ
Orszulak
T A
TA
Edwards
W D
WD
Tajik
J
J
Schwartz
R S
RS
D000818:Animals; D002275:Carcinoid Heart Disease / Q000473:pathology / Q000503:physiopathology*; D002468:Cell Physiological Phenomena / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004699:Endocardium / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology*; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006351:Heart Valves / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D066298:In Vitro Techniques; D007650:Ketanserin / Q000494:pharmacology; D008719:Methiothepin / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013552:Swine
D016166:Free Radical Scavengers; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D012701:Serotonin; D008719:Methiothepin; D007650:Ketanserin