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

• Published in: iScience Vol. 25; no. 3; p. 103973
• Main Authors: Kaur, Namrita, Ruiz-Velasco, Andrea, Raja, Rida, Howell, Gareth, Miller, Jessica M., Abouleisa, Riham R.E., Ou, Qinghui, Mace, Kimberly, Hille, Susanne S., Frey, Norbert, Binder, Pablo, Smith, Craig P., Fachim, Helene, Soran, Handrean, Swanton, Eileithyia, Mohamed, Tamer M.A., Müller, Oliver J., Wang, Xin, Chernoff, Jonathan, Cartwright, Elizabeth J., Liu, Wei
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.03.2022; Elsevier
• Subjects: Biological sciences; Cardiovascular medicine; Cell biology; Immunology; Cell biology; Biological sciences; Immunology; Cardiovascular medicine
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2022.103973

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 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 antidiabetic 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. [Display omitted] •In response to metabolic stress, loss of cardiac PAK2 leads to maladaptive ER stress•Cardiac CHOP-upregulated HMGB1 promotes M1 macrophage polarization by paracrine action•Pharmacological inhibition of HMGB1 decelerates myocardial inflammation•Vildagliptin and remediated ER alleviate cardiac dysfunction in diabetes Cardiovascular medicine; Biological sciences; Immunology; Cell biology