Inhibition of PHLPP1 ameliorates cardiac dysfunction via activation of the PI3K/Akt/mTOR signalling pathway in diabetic cardiomyopathy

Abstract

Background: Pleckstrin homology (PH) domain leucine-rich repeat protein phosphatase 1 (PHLPP1) is a kind of serine/threonine phosphatase, whose dysregulation is accompanied with numerous human diseases. However, its role in diabetic cardiomyopathy remains unclear. We explored the underlying function and mechanism of PHLPP1 in diabetic cardiomyopathy (DCM). Method:In vivo, Type 1 diabetic rats were induced by intraperitoneal injection of 60 mg/kg streptozotocin (STZ). Lentivirus-mediated short hairpin RNA (shRNA) was used to knock down the expression of PHLPP1. In vitro, primary neonatal rat cardiomyocytes and H9C2 cells were incubated in 5.5 mmol/L glucose (normal glucose, NG) or 33.3 mmol/L glucose (high glucose, HG). PHLPP1 expression was inhibited by PHLPP1-siRNA to probe into the function of PHLPP1 in high glucose-induced apoptosis in H9c2 cells.Results: Diabetic rats showed up-regulated PHLPP1 expression, left ventricular dysfunction, increased myocardial apoptosis and fibrosis. PHLPP1 inhibition alleviated cardiac dysfunction. Additionally, PHLPP1 inhibition significantly reduced HGinduced apoptosis and restored PI3K/AKT/mTOR pathway activity in H9c2 cells. Furthermore, pretreatment with LY294002, an inhibitor of PI3K/Akt/mTOR pathway, abolished the anti-apoptotic effect of PHLPP1 inhibition. Conclusion:Our study indicated that PHLPP1 inhibition alleviated cardiac dysfunction via activating the PI3K/Akt/mTOR signalling pathway in DCM. Therefore, PHLPP1 may be a novel therapeutic target for human DCM. K E Y W O R D S apoptosis, diabetic cardiomyopathy, fibrosis, PHLPP1, PI3K/Akt/mTOR signal | 4613 ZHANG et Al.

Pleckstrin homology (PH) domain and Leucine Rich Repeat Phosphatase 1 (Phlpp1) Suppresses Parathyroid Hormone Receptor 1 (Pth1r) Expression and Signaling During Bone Growth

“…Further enhancement of cell proliferation as a result of Phlpp1 inhibition has potential implications beyond chondrocytes. Phlpp1 deletion promotes cell proliferation in a model of intervertebral disc degeneration, (19 ) and regulation of cell apoptosis by Phlpp1 is implicated in ischemic brain and spinal cord injury, ( 20,22 ) colitis, ( 21 ) cardiac dysfunction, ( 66 ) pancreatic beta‐cell survival, ( 67 ) and tumor activity. ( 8 ) As such, enhancement of signals associated with Phlpp1 inhibition could have a profound impact on various physiological and disease processes.…”

Knockdown of lncRNA LINC01234 suppresses the tumorigenesis of liver cancer via sponging miR-513a-5p

“…Components of the PI3K/Akt pathway are targeted in more types of cancer than any other growth factor signaling pathway, and it is commonly activated as a cancer promoter (42). In our current research, LINC01234 knockdown significantly inactivated PI3K/Akt signaling.…”

Knockdown of lncRNA LINC01234 suppresses the tumorigenesis of liver cancer via sponging miR-513a-5p

“…Components of the PI3K/Akt pathway are targeted in more types of cancer than any other growth factor signaling pathway, and it is commonly activated as a cancer promoter (42). In our current research, LINC01234 knockdown signi cantly inactivated PI3K/Akt signaling.…”