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Mast Cells Modulate Cardiac Interstitial Angiotensin II levels by Regulating Interstitial ACE But Not Chymase Activity in Conscious Mice
Author(s) -
Wei Chihchang Kevin,
Shi Ke,
Bradley Wayne E,
Cain Laura J,
Husain Ahsan,
Dell’Italia Louis J
Publication year - 2007
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.21.6.a870-b
Subject(s) - chymase , medicine , endocrinology , mast cell , angiotensin ii , in vivo , interstitial fluid , chemistry , renin–angiotensin system , interstitial space , microdialysis , angiotensin converting enzyme , bradykinin , biology , immunology , receptor , blood pressure , microbiology and biotechnology , central nervous system
Non‐ACE pathway(s), including chymase, are thought to regulate angiotensin II (Ang II) formation in the cardiac interstitial fluid (ISF) space, while ACE regulates Ang II in the vascular lumen. In cardiac tissue homogenates from mast cell deficient (WBB6F1‐W/W(v), [MCD]) mice and their congenic mast cell sufficient littermates (WT), mast cells are the source of non‐ACE Ang II‐forming activity. Since chymase exists in mast cell granules and extracellularly, total chymase activity may not reflect its true ISF Ang II‐forming capacity. To study this, we used in vivo cardiac microdialysis in conscious mice with direct ISF infusion of ACE selective Ang I substrate [Pro10]Ang I (in vivo ISF ACE activity) and chymase selective Ang I substrate [Pro11, DAla12]Ang I (in vivo ISF chymase activity). ACE and chymase activities were equivalent in LV homogenates from MCD and WT mice. However, in WT mice, only ISF ACE activity was detectable but ISF chymase activity was not. In MCD mice, LV chymase activity was not detectable while ACE activity was increased 2.5‐fold over WT mice. Basal ISF Ang II was 2.5‐fold higher in MCD vs. WT and normalized by chronic captopril therapy. These studies demonstrate for the first time ACE‐mediated Ang II formation in cardiac ISF in vivo. Although mast cell deficiency causes a loss in LV tissue chymase activity, it upregulates tissue and ISF ACE activities and increases basal ISF Ang II. Thus, cardiac mast cells do not regulate ISF Ang II by directly increasing ISF nonACE activity, but rather by tonically suppressing ISF ACE activity and/or increasing ISF Ang II degradation. Supported by R01HL60707;54816(LJD); National AHA SDG0130306N(CCW), SCCOR in Cardiac Dysfunction P50HL077100.