Caveolin-1 ablation reduces the adverse cardiovascular effects of N-omega-nitro-L-arginine methyl ester and angiotensin II.
Caveolae are the major cellular membrane structure through which extracellular mediators transmit information to intracellular signaling pathways. In vascular tissue (but not ventricular myocardium), caveolin-1 (cav-1) is the main component of caveolae; cav-1 modulates enzymes and receptors, such as the endothelial nitric oxide synthase and the angiotensin II (AngII) type 1 receptor. Evidence suggests that AngII and aldosterone (ALDO) are important mediators of ventricular injury. We have described a model of biventricular damage in rodents that relies on treatment with N-omega-nitro-l-arginine methyl ester (L-NAME (nitric oxide synthase inhibitor)) and AngII. This damage initiated at the vascular level and was observed only in the presence of ALDO and an activated mineralocorticoid receptor (MR). We hypothesize that cav-1 modulates the adverse cardiac effects mediated by ALDO in this animal model. To test this hypothesis, we assessed the ventricular damage and measures of inflammation, in wild-type (WT) and cav-1 knockout (KO) mice randomized to either placebo or L-NAME/AngII treatment. Despite displaying cardiac hypertrophy at baseline and higher blood pressure responses to L-NAME/AngII, cav-1 KO mice displayed, as compared with WT, decreased treatment-induced biventricular damage as well as decreased transcript levels of the proinflammatory marker plasminogen activator inhibitor-1. Additionally, L-NAME/AngII induced an increase in cardiac MR levels in WT but not cav-1-ablated mice. Moreover and despite similar circulating ALDO levels in both genotypes, the myocardial damage (as determined histologically and by plasminogen activator inhibitor-1 mRNA levels) was less sensitive to ALDO levels in cav-1 KO vs. WT mice, consistent with decreased MR signaling in the cav-1 KO. Thus, we conclude that the L-NAME/AngII-induced biventricular damage is mediated by a mechanism partially dependent on cav-1 and signaling via MR/ALDO.
Pojoga
Luminita H
LH
Brigham and Women's Hospital/Harvard Medical School, Department of Endocrinology, Diabetes, and Hypertension, 221 Longwood Avenue, Boston, Massachusetts 02115, USA.
Romero
Jose R
JR
Yao
Tham M
TM
Loutraris
Paul
P
Ricchiuti
Vincent
V
Coutinho
Patricia
P
Guo
Christine
C
Lapointe
Nathalie
N
Stone
James R
JR
Adler
Gail K
GK
Williams
Gordon H
GH
D000450:Aldosterone / Q000097:blood*; D000595:Amino Acid Sequence; D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D051242:Caveolin 1 / Q000172:deficiency*; D042783:Endothelial Cells / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009206:Myocardium / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D015398:Signal Transduction
D051242:Caveolin 1; D044140:Receptor, Angiotensin, Type 1; D018161:Receptors, Mineralocorticoid; D000804:Angiotensin II; D000450:Aldosterone; D052250:Nitric Oxide Synthase Type III; D019331:NG-Nitroarginine Methyl Ester