Restored autophagy is protective against PAK3-induced cardiac dysfunction
Andrea Ruiz-Velasco,
Rida Raja,
Xinyi Chen,
Haresh Ganenthiran,
Namrita Kaur,
Nasser hawimel o Alatawi,
Jessica M. Miller,
Riham R.E. Abouleisa,
Qinghui Ou,
Xiangjun Zhao,
Oveena Fonseka,
Xin Wang,
Susanne S. Hille,
Norbert Frey,
Tao Wang,
Tamer M.A. Mohamed,
Oliver J. Müller,
Elizabeth J. Cartwright,
Wei Liu
Affiliations
Andrea Ruiz-Velasco
Faculty of Biology, Medicine, and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK
Rida Raja
Faculty of Biology, Medicine, and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK
Xinyi Chen
Faculty of Biology, Medicine, and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK
Haresh Ganenthiran
Faculty of Biology, Medicine, and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK
Namrita Kaur
Faculty of Biology, Medicine, and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK
Nasser hawimel o Alatawi
Faculty of Biology, Medicine, and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK
Jessica M. Miller
Institute of Molecular Cardiology, University of Louisville, 580 S Preston St, Louisville, KY 40202, USA
Riham R.E. Abouleisa
Institute of Molecular Cardiology, University of Louisville, 580 S Preston St, Louisville, KY 40202, USA
Qinghui Ou
Institute of Molecular Cardiology, University of Louisville, 580 S Preston St, Louisville, KY 40202, USA
Xiangjun Zhao
Faculty of Biology, Medicine, and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK
Oveena Fonseka
Faculty of Biology, Medicine, and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK
Xin Wang
Faculty of Biology, Medicine, and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK
Susanne S. Hille
Department of Internal Medicine III, University of Kiel, Kiel, Germany; DZHK, German Centre for Cardiovascular Research, Partner Site Hamburg/Kiel/Lübeck, Kiel, Germany
Norbert Frey
Department of Internal Medicine III, University of Kiel, Kiel, Germany; DZHK, German Centre for Cardiovascular Research, Partner Site Hamburg/Kiel/Lübeck, Kiel, Germany
Tao Wang
Faculty of Biology, Medicine, and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK
Tamer M.A. Mohamed
Institute of Molecular Cardiology, University of Louisville, 580 S Preston St, Louisville, KY 40202, USA
Oliver J. Müller
Department of Internal Medicine III, University of Kiel, Kiel, Germany; DZHK, German Centre for Cardiovascular Research, Partner Site Hamburg/Kiel/Lübeck, Kiel, Germany
Elizabeth J. Cartwright
Faculty of Biology, Medicine, and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK
Wei Liu
Faculty of Biology, Medicine, and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK; Corresponding author
Summary: Despite the development of clinical treatments, heart failure remains the leading cause of mortality. We observed that p21-activated kinase 3 (PAK3) was augmented in failing human and mouse hearts. Furthermore, mice with cardiac-specific PAK3 overexpression exhibited exacerbated pathological remodeling and deteriorated cardiac function. Myocardium with PAK3 overexpression displayed hypertrophic growth, excessive fibrosis, and aggravated apoptosis following isoprenaline stimulation as early as two days. Mechanistically, using cultured cardiomyocytes and human-relevant samples under distinct stimulations, we, for the first time, demonstrated that PAK3 acts as a suppressor of autophagy through hyper-activation of the mechanistic target of rapamycin complex 1 (mTORC1). Defective autophagy in the myocardium contributes to the progression of heart failure. More importantly, PAK3-provoked cardiac dysfunction was mitigated by administering an autophagic inducer. Our study illustrates a unique role of PAK3 in autophagy regulation and the therapeutic potential of targeting this axis for heart failure.