Nitric Oxide‐cGMP‐PKG Pathway Acts on Orai1 to Inhibit the Hypertrophy of Human Embryonic Stem Cell‐Derived Cardiomyocytes. (12th August 2015)

• Record Type: Journal Article
• Authors: Wang, Y.; Li, Z. C.; Zhang, P.; Poon, E.; Kong, C. W.; Boheler, K. R.; Huang, Y.; Li, R. A.; Yao, X.
• Is Part Of: Stem cells. Volume 33:Number 10(2015:Oct.)
• Page Start: 2973
• Page End: 2984
• Publication Date: 2015-08-12
• Subjects: Orai1 -- Cardiomyocytes -- Hypertrophy -- Ca2+ -- Human embryonic stem cells; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.2118
• Languages: English
• ISSNs: 1066-5099

Abstract

Abstract: Cardiac hypertrophy is an abnormal enlargement of heart muscle. It frequently results in congestive heart failure, which is a leading cause of human death. Previous studies demonstrated that the nitric oxide (NO), cyclic GMP (cGMP), and protein kinase G (PKG) signaling pathway can inhibit cardiac hypertrophy and thus improve cardiac function. However, the underlying mechanisms are not fully understood. Here, based on the human embryonic stem cell‐derived cardiomyocyte (hESC‐CM) model system, we showed that Orai1, the pore‐forming subunit of store‐operated Ca 2+ entry (SOCE), is the downstream effector of PKG. Treatment of hESC‐CMs with an α‐adrenoceptor agonist phenylephrine (PE) caused a marked hypertrophy, which was accompanied by an upregulation of Orai1. Moreover, suppression of Orai1 expression/activity using Orai1‐siRNAs or a dominant‐negative construct Orai1 G98A inhibited the hypertrophy, suggesting that Orai1‐mediated SOCE is indispensable for the PE‐induced hypertrophy of hESC‐CMs. In addition, the hypertrophy was inhibited by NO and cGMP via activating PKG. Importantly, substitution of Ala for Ser 34 in Orai1 abolished the antihypertrophic effects of NO, cGMP, and PKG. Furthermore, PKG could directly phosphorylate Orai1 at Ser 34 and thus prevent Orai1‐mediated SOCE. Together, we conclude that NO, cGMP, and PKG inhibit the hypertrophy of hESC‐CMs via PKG‐mediated phosphorylation on Orai1‐Ser‐34. These results provide novel mechanistic insights into the action of cGMP‐PKG‐related antihypertrophic agents, such as NO donors and sildenafil. Stem Cells 2015;33:2973–2984