Mast Cells Contribute to Pressure Overload-Induced Myocardial Hypertrophy by Upregulating TRPV4 via Histamine: Role of Ca2+/ CnA/NFATc3 Signaling Pathway

Abstract

Objective

To investigate whether cardiac mast cells (MCs) participate in pressure overload-induced myocardial hypertrophy through the regulation of transient receptor potential vanilloid 4 (TRPV4).

Methods

Pressure overload-induced myocardial hypertrophy was induced via abdominal aortic constriction (AAC). Myocardial hypertrophy was evaluated by measuring the heart weight index (HW/BW), lung weight index (LW/BW), ratio of heart weight to tibia length (HW/TL), ratio of lung weight to tibia length (LW/TL), and cross-sectional area of myocardial cells. qRT-PCR was used to detect the mRNA expression of TRPV4. Western blotting was used to detect the protein expression of TRPV4, mast cell tryptase, myosin heavy chain beta (β-MHC), calcineurin A (CnA), and nuclear factor of activated T-cell c3 (NFATc3). ELISA was used to measure the levels of brain natriuretic peptide (BNP) and histamine. Fluo4 AM was used to detect the calcium signal in H9c2 myocardial cells.

Results

Compared with those of the sham rats, the myocardial mast cells, tryptase, HW/BW, LW/BW, HW/TL, and LW/TL, the cross-sectional area of the myocardial cells, and the expression of β-MHC, TRPV4, CnA, and NFATc3 in the myocardial tissue and the serum BNP of the AAC-treated rats increased significantly, whereas the MC stabilizer cromolyn sodium (CS) reversed these indicators. In H9c2 cardiomyocytes, treatment with histamine and the TRPV4 agonist GSK1016790A upregulated the expression of TRPV4, β-MHC, BNP, CnA and NFATc3 and increased calcium ion influx, whereas these effects were inhibited by the H2 receptor inhibitor famotidine and the TRPV4 inhibitor HC067047.

Conclusion

Cardiac MCs participate in pressure overload-induced myocardial hypertrophy through the upregulation of TRPV4 via its mediator histamine, and the Ca²⁺/CnA/NFATc3 signaling pathway is involved in this process.

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Huazhong University of Science and Technology