Cardiac Overexpression of the Human P2X4 Receptor Exhibits an Anti‐hypertrophic Phenotype

Abstract

Cardiac-specific overexpression of the human P2X4 receptor (hP2X4R) rescues the calsequestrin (CSQ) overexpression model of heart failure (Am. J. Physiol. 287: H1096-H1103, 2004). The mechanism by which P2X4R overexpression rescues heart failure is unknown. Our objective was to test the hypothesis that reversal or attenuation of hypertrophy is a mechanism that underlies the beneficial effect of the P2X4R overexpression. In age-matched animals (~ 12 weeks), the CSQ mice showed significantly enlarged hearts with elevated heart/body weight ratio (15.1±0.9 mg/g, n=6, ± SD) as compared to the binary (9.1 ± 1.4), non-transgenic (NTG) (4.8±0.1, n=8) or P2X4R (4.7±0.3, n=8) animals (P<0.01). Cell length and cross-sectional area of cardiac myocytes were quantified as indices of myocyte hypertrophy. Cell length of binary mice (150.6 ± 1.6 μm, n=54) was significantly less than that of the CSQ mice (157.7 ± 2.1 μm, n=60 cells, ± SE, P<0.05). Similarly, myocyte cross section area was significantly reduced in binary (229.6 ± 4.1) vs. CSQ (349.6 ± 5.9) mice (P<0.01). Conclusion: Reversal of hypertrophy, arising from decreases in both myocyte size and extracellular collagen content, is a mechanism by which the heart failure is rescued in this model of severe cardiomyopathy.