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Direct interaction of angiotensin‐II type 1 receptor (AT1) and NOX2 mediates TCF/LEF and CREB activation, WISP1 induction, and cardiomyocyte hypertrophy
Author(s) -
Shanmugam Prakashsrinivasan,
Prabhu Sumanth D,
Valente Anthony J,
Venkatesan Balachandar,
Hazari Sidhartha,
Chandrasekar Bysani
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.365.7
Angiotensin‐II (Ang‐II) plays a key role in myocardial remodeling and hypertrophy. Wnt‐Induced Signaling Pathway Protein‐1 (WISP1), a CCN family member, is a pro‐survival and pro‐growth factor. We investigated whether Ang‐II‐induced cardiomyocyte hypertrophy is WISP1 dependent. Our results show that Ang‐II mediates cardiomyocyte hypertrophy as evidenced by increased cell surface area and protein synthesis, and these effects were blocked by WISP1 knockdown. Ang‐II induces WISP1 expression, an effect that was significantly inhibited by pre‐treatment with losartan, an AT1 antagonist, or NOX2 knockdown. Further investigations revealed that AT1 physically associates with NOX2, and mediates Ang‐II‐induced WISP1 expression via superoxide dependent Akt/GSK3β/β‐catenin/TCF/LEF, and p38MAPK‐ and ERK‐mediated CREB activation. Treatment with WISP1 recapitulated Ang‐II pro‐growth effects, and induced activation of PI3K, Akt, p70 S6K and ribosomal S6 protein, and cardiomyocyte hypertrophy. Continuous infusion of Ang‐II for one week induced myocardial hypertrophy and upregulated WISP1 expression in vivo. These results demonstrate a crosstalk between RAS, NOX, and the CCN family, and AT1 and NOX2 protein‐protein interaction in cardiomyocyte hypertrophy. Thus, WISP1 has the therapeutic potential in cardiomyocyte survival and growth following myocardial injury and remodeling.