Paracrine signal emanating from stressed cardiomyocytes aggravates inflammatory microenvironment in diabetic cardiomyopathy

Namrita Kaur, Andrea Ruiz-velasco, Rida Raja, Gareth Howell, Jessica M. Miller, Riham R.e. Abouleisa, Qinghui Ou, Kimberly Mace, Susanne S. Hille, Norbert Frey, Pablo Binder, Craig P. Smith, Helene Fachim, Handrean Soran, Eileithyia Swanton, Tamer M.a. Mohamed, Oliver J. Müller, Xin Wang, Jonathan Chernoff, Elizabeth J. CartwrightWei Liu

Research output: Contribution to journalArticlepeer-review


Myocardial inflammation contributes to cardiomyopathy in diabetic patients through incompletely-defined underlying mechanisms. In both human and time-course experimental samples, diabetic hearts exhibited abnormal endoplasmic reticulum (ER), with a maladaptive shift over time in rodents. Furthermore, as a cardiac ER dysfunction model, mice with cardiac-specific p21-activated kinase 2 (PAK2) deletion exhibited heightened myocardial inflammatory response in diabetes. Mechanistically, maladaptive ER stress-induced CCAAT/enhancer-binding protein homologous protein (CHOP) is a novel transcriptional regulator of cardiac high mobility group box-1 (HMGB1). Cardiac stress-induced release of HMGB1 facilitates M1 macrophage polarization, aggravating myocardial inflammation. Therapeutically, sequestering the extracellular HMGB1 using Glycyrrhizin conferred cardioprotection through its anti-inflammatory action. Our findings also indicated that an intact cardiac ER function and protective effects of the anti-diabetic drug interdependently attenuated the cardiac inflammation-induced dysfunction. Collectively, we introduce an ER stress-mediated cardiomyocyte-macrophage link, altering the macrophage response, thereby providing insight into therapeutic prospects for diabetes-associated cardiac dysfunction.
Original languageEnglish
Article number103973
Pages (from-to)103973
Issue number3
Early online date23 Feb 2022
Publication statusPublished - 23 Feb 2022


  • Biological sciences
  • Cardiovascular medicine
  • Cell biology
  • Immunology


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