Magnesium supplementation prevents angiotensin II-induced myocardial damage and CTGF overexpression.
OBJECTIVE
Magnesium deficiency promotes vasoconstriction and myocardial damage. Recent studies provide evidence that Ang II mobilizes intracellular Mg through AT1 receptor-mediated pathways. We tested the hypothesis of whether magnesium supplementation prevents Ang II-induced myocardial damage and induction of the profibrotic connective tissue growth factor (CTGF).


METHODS
Four-week-old double transgenic rats harboring human renin and angiotensinogen genes (dTGR) were given dietary magnesium supplementation (0.6%) for 3 weeks. Control dTGR and normotensive Sprague-Dawley (SD) rats received normal diet (Mg 0.2%). Histopathological, immunohistochemical and mRNA analysis were used to detect the treatment-related effects of dietary magnesium in dTGR.


RESULTS
Magnesium (Mg) supplementation decreased blood pressure, ameliorated cardiac hypertrophy, protected against the development of Ang II-induced myocardial damage and increased serum ionized Mg2+ concentration (all variables P < 0.05). There was no difference in serum ionized Mg2+ concentration between dTGR and SD rats. Myocardial connective tissue growth factor (CTGF) mRNA and protein expressions were increased by 300% in dTGR (P < 0.05), especially in areas with myocardial infarctions and vascular inflammation. Magnesium supplementation prevented Ang II-induced myocardial CTGF overexpression (P < 0.05). Magnesium supplementation also improved the therapeutic effects of the calcineurin inhibitor tacrolimus, which produced marked hypomagnesemia when given as monotherapy.


CONCLUSIONS
Our findings suggest a salutary effect for magnesium supplementation in the treatment of Ang II-induced myocardial complications.
Finckenberg
Piet
P
Institute of Biomedicine, Pharmacology, University of Helsinki, P.O. Box 63, FIN-00014, Finland.
Merasto
Saara
S
Louhelainen
Marjut
M
Lindgren
Leena
L
Vapaatalo
Heikki
H
Müller
Dominik N
DN
Luft
Friedrich C
FC
Mervaala
Eero M A
EM
D000804:Angiotensin II / Q000494:pharmacology*; D000808:Angiotensinogen / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000628:therapy; D055513:Connective Tissue Growth Factor; D019587:Dietary Supplements; D005355:Fibrosis / Q000517:prevention & control; D006801:Humans; D017874:Immediate-Early Proteins / Q000187:drug effects / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008274:Magnesium / Q000008:administration & dosage* / Q000097:blood / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000235:genetics; D016559:Tacrolimus / Q000627:therapeutic use
C526317:CCN2 protein, human; C526316:CCN2 protein, rat; D017874:Immediate-Early Proteins; D007166:Immunosuppressive Agents; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D000808:Angiotensinogen; D000804:Angiotensin II; D055513:Connective Tissue Growth Factor; D012083:Renin; D008274:Magnesium; D016559:Tacrolimus