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The Role of CaMKIId in Angiotensin II‐Induced Cardiac Inflammation and Fibrosis
Author(s) -
Willeford Andrew
Publication year - 2016
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.30.1_supplement.718.2
Subject(s) - inflammation , angiotensin ii , fibrosis , cardiac fibrosis , ctgf , medicine , heart failure , endocrinology , angiotensin receptor , mediator , proinflammatory cytokine , receptor , growth factor
The Ca 2+ /calmodulin‐dependent kinase, CaMKIId, is an established mediator of the development of heart failure and myocardial injury. Cardiac inflammation has been increasingly recognized as an important player in these cardiac pathophysiological changes. We previously demonstrated that CaMKIId contributes to cardiac inflammation induced by ischemia/reperfusion through activation of cardiomyocyte nuclear factor kappa B (NF‐kB). In the current study we ask whether angiotensin II (Ang II) promotes cardiac inflammation through CaMKIId and its effects on NF‐kB activation. In addition, Ang II treatment promotes cardiac fibrosis and we hypothesize that this response is initiated through activation of CaMKIId in the cardiomyocyte and subsequent inflammatory responses. Here, we report on preliminary data demonstrating attenuation of inflammatory gene expression (e.g. MCP‐1, MIP1a, IL‐6, TNFa) in cardiomyocyte‐specific CaMKIId KO (CKO) mice following 1 and 7 days of Ang II infusion. In addition, the expression of fibrotic markers (e.g. col1a1, col3a1, TGFβ, and CTGF) in response to Ang II infusion is decreased in CKO mice following 7 days of infusion. This is associated with attenuated fibrosis as evident in histological analysis of CKO vs control heart sections. To note, we do not see increased expression of fibrotic markers after 1 day Ang II infusion, suggesting that inflammation precedes fibrosis. Furthermore, we have demonstrated that inhibition of CCR2, the receptor for MCP‐1, attenuates inflammatory gene expression induced by 1 day of Ang II infusion. Currently, we are determining whether Ang II acts through CaMKIId in the cardiomyocyte to activate NF‐kB‐mediated MCP‐1 gene transcription and whether blockade of CCR2 is sufficient to attenuate Ang II‐induced fibrosis. Findings from these studies may implicate CaMKIId as a promising therapeutic target for attenuating cardiac fibrosis. Support or Funding Information Pharmacology Training Grant (2T32‐GM007752) and UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences