Reversal of cardiac myocyte dysfunction as a unique mechanism of rescue by P2X₄ receptors in cardiomyopathy

Abstract

Binary cardiac transgenic (Tg) overexpression of P2X(4) receptors (P2X(4)R) improved the survival of the cardiomyopathic calsequestrin (CSQ) mice. Here we studied the mechanism of rescue using binary P2X(4)R/CSQ Tg and CSQ Tg mice as models. Cellular and intact heart properties were determined by simultaneous sarcomere shortening (SS) and Ca(2+) transients in vitro and echocardiography in vivo. Similar to a delay in death, binary mice exhibited a slowed heart failure progression with a greater left ventricular (LV) fractional shortening (FS) and thickness and a concomitant lesser degree of LV dilatation in both systole and diastole at 8 or 12 wk. By 16 wk, binary hearts showed similarly depressed FS and thinned out LV and equal enlargement of LV as did 12-wk-old CSQ hearts. Binary cardiac myocytes showed higher peak basal cell shortening (CS) and SS as well as greater basal rates of shortening and relaxation than did the CSQ myocytes at either 8 or 12 wk. Similar data were obtained in comparing the Ca(2+) transient. At 16 wk, binary myocytes were like the 12-wk-old CSQ myocytes with equally depressed CS, SS, and Ca(2+) transient. CSQ myocytes were longer than myocytes from wild-type and binary mice at 12 wk of age. At 16 wk, the binary myocyte length increased to that of the 12-wk-old CSQ myocyte, parallel to LV dilatation. The data suggest a unique mechanism, which involves a reversal of cardiac myocyte dysfunction and a delay in heart failure progression. It represents an example of targeting the abnormal failing myocyte in treating heart failure.

Treatment of Heart Failure by a Methanocarba Derivative of Adenosine Monophosphate: Implication for a Role of Cardiac Purinergic P2X Receptors

“…Consistent with improved systolic contractile function, the forward output was also greater in MRS2339-infused than in vehicleinfused CSQ mice. By in vivo heart function measure, the FS was also similarly improved in CSQ animals infused with MRS2339 (current data) and those overexpressing the P2X 4 R (Shen et al, 2009). The present data showed that the HF rescuing effect by either MRS2339 infusion or cardiac overexpression of P2X 4 R was associated with a better preservation of LV wall thickness during systole and diastole in both mouse models.…”

“…Much of the evidence was based on a salutary phenotype in mice with HF with transgenic overexpression of the P2X 4 R (Yang et al, 2004;Sonin et al, 2008;Shen et al, 2009), an important subunit of the endogenous cardiac P2X receptor (Shen et al, 2006). The role of the endogenous cardiac P2X receptor and characterization of its action in improving HF are poorly understood.…”

“…Transthoracic echocardiography was performed with a linear 30-MHz transducer according to the manufacturer's instructions (Vevo 660 High-Resolution Imaging System, VisualSonics, Toronto, Canada) as described previously (Hu et al, 2001;Sonin et al, 2008;Shen et al, 2009). Two-dimensional-targeted M-mode echocardiographic measurements were carried out at midpapillary muscle level.…”

“…Recent evidence suggests that P2X receptors (P2XRs) may play an important biological role in the heart. Mice with cardiac-specific overexpression of the P2X 4 R [P2X 4 R transgenic (Tg) mice], which is an important subunit of the native cardiac myocyte P2XR (Shen et al, 2006), displayed an enhanced basal contractile function (Hu et al, 2001) and protected against the progression of HF (Yang et al, 2004;Sonin et al, 2008;Shen et al, 2009). Mice overexpressing calsequestrin (CSQ) develop dilated cardiomyopathy and die prematurely of HF (Jones, etal., 1998).…”

Cardiac P2X 4 Receptors

“…14,15 To activate endogenous P2X 4 receptors in mice with heart failure, a hydrolysis-resistant adenine nucleotide (MRS2339) with agonist activity at cardiomyocyte P2X 4 receptors was infused chronically in calsequestrin-overexpressing and postinfarct heart failure mice as well as in dogs with pacing-induced heart failure. MRS2339 infusion at low dosage was able to protect these animals with heart failure, similar to the protective effect exerted by cardiac-specific transgenic overexpression of the P2X 4 receptor.…”