title: Class III PI3K-mediated prolonged activation of autophagy plays a critical role in the transition of cardiac hypertrophy to heart failure.
abstract: Pathological cardiac hypertrophy often leads to heart failure. Activation of autophagy has been shown in pathological hypertrophic hearts. Autophagy is regulated positively by Class III phosphoinositide 3-kinase (PI3K). However, it is unknown whether Class III PI3K plays a role in the transition of cardiac hypertrophy to heart failure. To address this question, we employed a previously established cardiac hypertrophy model in heat shock protein 27 transgenic mice which shares common features with several types of human cardiomyopathy. Age-matched wild-type mice served as control. Firstly, a prolonged activation of autophagy, as reflected by autophagosome accumulation, increased LC3 conversion and decreased p62 protein levels, was detected in hypertrophic hearts from adaptive stage to maladaptive stage. Moreover, morphological abnormalities in myofilaments and mitochondria were presented in the areas accumulated with autophagosomes. Secondly, activation of Class III PI3K Vacuolar protein sorting 34 (Vps34), as demonstrated by upregulation of Vps34 expression, increased interaction of Vps34 with Beclin-1, and deceased Bcl-2 expression, was demonstrated in hypertrophic hearts from adaptive stage to maladaptive stage. Finally, administration with Wortmaninn, a widely used autophagy inhibitor by suppressing Class III PI3K activity, significantly decreased autophagy activity, improved morphologies of intracellular apartments, and most importantly, prevented progressive cardiac dysfunction in hypertrophic hearts. Collectively, we demonstrated that Class III PI3K plays a central role in the transition of cardiac hypertrophy to heart failure via a prolonged activation of autophagy in current study. Class III PI3K may serve as a potential target for the treatment and management of maladaptive cardiac hypertrophy.
authors: Department of Geriatrics, First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
authors: Peng
authors: P
authors: Yu
authors: Department of Geriatrics, First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
authors: Yangyang
authors: Y
authors: Zhang
authors: Department of Surgery, East Tennessee State University, Johnson City, TN, USA.
authors: Chuanfu
authors: C
authors: Li
authors: Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors: Yuehua
authors: Y
authors: Li
authors: Department of Geriatrics, First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
authors: Surong
authors: S
authors: Jiang
authors: Department of Geriatrics, First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
authors: Xiaojin
authors: X
authors: Zhang
authors: Department of Anesthesiology, First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
authors: Zhengnian
authors: Z
authors: Ding
authors: Department of Geriatrics, First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
authors: Fei
authors: F
authors: Tu
authors: Department of Geriatrics, First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
authors: Jun
authors: J
authors: Wu
authors: Model Animal Research Center, Nanjing University, Nanjing, China.
authors: Xiang
authors: X
authors: Gao
authors: Department of Geriatrics, First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
authors: Liu
authors: L
authors: Li
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D000071186:Beclin-1; D006332:Cardiomegaly / Q000150:complications / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000473:pathology; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D006333:Heart Failure / Q000150:complications / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000473:pathology; D006334:Heart Function Tests; D006801:Humans; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D014463:Ultrasonography; D015854:Up-Regulation / Q000187:drug effects; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D055551:HSP27 Heat-Shock Proteins; D047428:Protein Kinase Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D000077191:Wortmannin
keywords: Class III PI3K Vps34; autophagy; cardiac hypertrophy; heart failure; heat shock protein 27