Calcium- and superoxide anion-mediated mitogenic action of substance P on cardiac fibroblasts.
Substance P is released from nerve endings in the heart under pathological conditions like ischemia, but its action on cardiac cells has not been investigated. This study tested the hypothesis that substance P is mitogenic to adult cardiac fibroblasts and delineated the underlying mechanism(s). Substance P, acting via neurokinin-1 (NK-1) receptors, stimulated cellular hyperplasia over a range of 1-10 micromol/l. It elicited no change in net collagen production, total protein synthesis, or cell protein content but increased (45)Ca uptake and superoxide generation. EGTA, N-acetyl-cysteine, and superoxide dismutase attenuated the hyperplastic response to substance P. A combination of substance P and EGTA enhanced superoxide generation without an increase in DNA synthesis, showing that an increase in superoxide production does not result in hyperplasia when extracellular Ca(2+) is chelated. Together, the data suggest that substance P may activate, via NK-1 receptors, a hyperplastic but not hypertrophic response in adult cardiac fibroblasts and that alterations in redox state and Ca(2+) homeostasis may act in concert to mediate its mitogenic action.
Kumaran
C
C
Division of Cellular and Molecular Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, India 695 011.
Shivakumar
K
K
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects*; D002614:Chelating Agents / Q000494:pharmacology; D003094:Collagen / Q000096:biosynthesis; D004533:Egtazic Acid / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology*; D006706:Homeostasis; D008934:Mitogens / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology*; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000187:drug effects / Q000502:physiology; D013373:Substance P / Q000008:administration & dosage / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*
D002614:Chelating Agents; D008934:Mitogens; D018040:Receptors, Neurokinin-1; D013481:Superoxides; D013373:Substance P; D004533:Egtazic Acid; D003094:Collagen; D013482:Superoxide Dismutase; D002118:Calcium; D000111:Acetylcysteine