Role of PKA in the process of neonatal cardiomyocyte hypertrophy induced by urotensin II

Abstract

The model of urotensin II (UII)-induced cardiomyocyte hypertrophy has been widely used in studies on hypertrophy. However, the molecular mechanisms responsible for UII-induced cardiomyocyte hypertrophy have not yet been fully elucidated. It has been demonstrated that cardiomyocyte hypertrophy induced by UII is associated with changes in the intracellular Ca2+ concentration. In the present study, we investigated whether the cAMP-dependent protein kinase A (PKA)‑mediated upregulation of the phosphorylation levels of phospholamban (PLN) at Ser16 contributes to UII-induced cardiomyocyte hypertrophy. After primary cultures of neonatal rat cardiomyocytes were exposed to UII for 48 h, cell size, protein/DNA contents and intracellular Ca2+ levels were detected. Western blot analysis was used to quantify the phosphorylated and total forms of PKA, PLN and the total amount of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA)2a. UII increased the cell size, the protein/DNA ratio and the intracellular Ca2+ levels, consistent with the characteristics of hypertrophic response. In addition, exposure to UII upregulated the phosphorylation levels of PKA, and the expression levels of its downstream proteins, PLN and SERCA2a. However, treatment with PKA inhibitor (KT-5720) reversed all these effects of UII. On the whole, our results suggest that UII induces cardiomyocyte hypertrophy through the PKA-mediated upregulation of PLN phosphorylation at Ser16, which provides a new experimental foundation for the prevention and/or treatment of cardiac hypertrophy.

Birth Weight Standard Deviation Score is a Significant Determinant of Serum Urotensin-II Levels at Term-Equivalent Age in Preterm Infants

“…28 Moreover, U-II induces proliferation of vascular smooth muscle cells 10 and cardiomyocytes. 11 Indeed, previous studies have indicated the presence of cardiac hypertrophy 29 and altered cardiac function 30 in SGA infants. These findings imply that increased levels of serum U-II in preterm infants with lower birth weight SD scores might be associated with an increased risk of hypertension and atherosclerosis in the future.…”

“…10 Other reports indicate that U-II has a similar effect on cardiomyocyte, resulting in cardiohypertrophy. 11 Moreover, U-II acts as an inflammatory cytokine, which may unify the molecular basis of the innate immune and inflammatory response. 12 Elevated plasma U-II levels were detected in adults with atherosclerosis, 10 hypertension, 13 14 and congestive heart failure, 15 although other studies reported inconsistent results.…”

Intermedin protects thapsigargin‑induced endoplasmic reticulum stress in cardiomyocytes by modulating protein kinase A and sarco/endoplasmic reticulum Ca2+‑ATPase

“…Therefore, the preset study focused on the role of IMD in thapsigargin-induced cardiomyocyte apoptosis and examined SERCA activity during thapsigargin treatment to explore whether IMD restored ER stress in cardiomyocytes via a SERCA-dependent mechanism. Protein kinase A (PKA) has also been reported to increase SERCA activity (21); to further explore the underlying mechanisms through which IMD regulates SERCA activity and ER stress, the present study examined the involvement of the PKA pathway in the IMD-mediated protective effects in cardiomyocytes.…”

“…PKA contributes to SERCA function and ER stress regulated by IMD. As PKA regulates PLB phosphorylation and SERCA activity (21,26), the present study further examined whether the PKA signaling pathway was involved in IMD-mediated cardioprotection, PLB phosphorylation and SERCA function. As presented in Fig.…”

Urotensin II: an inflammatory cytokine

“…In addition, UII also induces endothelial cell expression of eNOS and increases the release of vasodilating prostacyclin and PGE 2 into the blood, resulting in vasodilatation (Zhang et al 2003, Ishihata et al 2005. In the heart, UII can enhance the cardiotoxic oxidative stress response (Rahimi et al 2018) and increase PKA activity to induce the hypertrophy of neonatal cardiac myocytes (Xu et al 2017). It also plays an important role in the development of adult hypertrophic cardiomyopathy (Jumaah et al 2018) and rheumatic valvular disease (Elmadbouh et al 2017).…”