Restored autophagy is protective against PAK3-induced cardiac dysfunction

Andrea Ruiz Velasco Hernandez, 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 Hille, Norbert Frey, Tao Wang, Tamer Mohamed, Oliver J. Müller, Elizabeth Cartwright, Wei Liu

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Publication statusAccepted/In press - 23 May 2023


  • Heart Failure
  • Cell Signaling/Cell Transduction
  • autophagy
  • Translational studies


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