Cardiac thromboxane A2 receptor activation does not directly induce cardiomyocyte hypertrophy but does cause cell death that is prevented with gentamicin and 2-APB

Abstract

BackgroundWe have previously shown that the thromboxane (TXA2) receptor agonist, U46619, can directly induce ventricular arrhythmias that were associated with increases in intracellular calcium in cardiomyocytes. Since TXA2 is an inflammatory mediator and induces direct calcium changes in cardiomyocytes, we hypothesized that TXA2 released during ischemia or inflammation could also cause cardiac remodeling.MethodsU46619 (0.1-10 μM) was applied to isolated adult mouse ventricular primary cardiomyocytes, mouse ventricular cardiac muscle strips, and cultured HL-1 cardiomyocytes and markers of hypertrophy and cell death were measured.ResultsWe found that TXA2 receptors were expressed in ventricular cardiomyocytes and were functional via calcium imaging. U46619 treatment for 24 h did not increase expression of pathological hypertrophy genes (atrial natriuretic peptide, β-myosin heavy chain, skeletal muscle α-actin) and it did not increase protein synthesis. There was also no increase in cardiomyocyte size after 48 h treatment with U46619 as measured by flow cytometry. However, U46619 (0.1-10 μM) caused a concentration-dependent increase in cardiomyocyte death (trypan blue, MTT assays, visual cell counts and TUNEL stain) after 24 h. Treatment of cells with the TXA2 receptor antagonist SQ29548 and inhibitors of the IP3 pathway, gentamicin and 2-APB, eliminated the increase in cell death induced by U46619.ConclusionsOur data suggests that TXA2 does not induce cardiac hypertrophy, but does induce cell death that is mediated in part by IP3 signaling pathways. These findings may provide important therapeutic targets for inflammatory-induced cardiac apoptosis that can lead to heart failure.

Antagonism of the Thromboxane‐Prostanoid Receptor is Cardioprotective against Right Ventricular Pressure Overload

“…By immunostaining, the TP receptor localized primarily to cardiomyocytes in the RV, similar to the gene and protein expression demonstrated by others 15 , 17 . We also demonstrate here an upregulated cell surface expression of the TP receptor in RV from patients with PAH, a finding in accord with the radioligand binding work of Katugampola and Davenport 16 .…”

“…demonstrated by others. 15,17 We also demonstrate here an upregulated cell surface expression of the TP receptor in RV from patients with PAH, a finding in accord with the radioligand binding work of Katugampola and Davenport. 16 Human TPα receptor expression can be augmented posttranslationally by reactive oxygen species in a feed-forward mechanism, 24 which would correspond with both the pattern of expression seen in patients with PAH as well as availability of an isoprostane ligand.…”

“…One group has found that stimulation of the TP receptor dose-dependently causes DNA fragmentation and cell death in cultured primary cardiomyocytes. 15 These effects were reversed with a TP receptor antagonist, suggesting that CPI211 treatment could prevent cell death in the RV during pressure overload; however, additional studies will be needed to ascertain this possibility. Reduced TGFβ activity is probably partially responsible for the diminished fibrotic response, although the CPI211-initiated event behind the decrease in active TGFβ is yet unknown.…”

“…[9][10][11] The cyclooxygenase products of cyclic endoperoxide and thromboxane A 2 (TxA 2 ) are also ligands of the TP receptor, and TP receptor activation contributes to cardiac hypertrophy in models of chronic hypertension 12,13 and decreases cardiac function in Gh-overexpressing mice. 14 The TP receptor is found not only in platelets and vessels but also in mouse and rat ventricular cardiomyocytes 15 and the human RV, where receptor density is increased in patients with PAH. 16 This G protein-coupled receptor can signal through G αq/11 or G α12/13 subunits, and so receptor activation can result in increased intracellular calcium; in cardiomyocytes, this may contribute to arrhythmia.…”

Piperazine ferulate exerts antihypertensive effect and improves endothelial function in vitro and in vivo via the activation of endothelial nitric oxide synthase

“…Nitric oxide (NO) increases cyclic guanosine monophosphate (cGMP) levels in smooth muscle cells via the activation of guanylate cyclase which stimulates adenylate cyclase. This increases the intracellular levels of cyclic adenosine monophosphate (cAMP), thus, relaxing smooth muscle cells and dilating blood vessels (22). Reduced levels of these endothelium-derived vasodilators as seen in hypertension and diabetes, increase the levels of endothelium-derived contractile factors in blood vessels, thereby aggravating vascular endothelial dysfunction (23).…”