Regulatory Role of Sectm1a in Macrophages to Treat Diabetes‐Induced Cardiac Dysfunction
Authors: Li Yutian , Deng Shan , Wang Xiaohong , Robbins Nathan , Mu Xingjiang , Essandoh Kobina , Rubinstein Jack , Fan Guo‐Chang 
Published: June 2021

BackgroundRecent studies have indicated that macrophage polarization plays major role in the pathophysiology of diabetes‐induced cardiomyopathy. Current view shows that M1 macrophages (pro‐inflammatory) are enhanced while M2 macrophages (anti‐inflammatory) are reduced in diabetic patients. Nonetheless, how to modulate macrophage polarization in diabetic conditions remains unclear. Secreted and transmembrane protein 1a (Sectm1a) is mainly expressed in immune cells of myeloid lineage and epithelial cells, however, to our knowledge, the functional role of Sectm1a in macrophages or diabetes has never been investigated.MethodsDiabetes was induced in wild‐type (WT) or Sectm1a knockout (KO, C57Bl6 background) mice by either daily intraperitoneal injection of streptozotocin (STZ, 50 mg/kg body weight) for 5 days (type 1 diabetes, T1D), or 60% high fat diet (HFD, T2D) feeding for 18 weeks. Cardiac dysfunction was assessed by echocardiography. Expression of genes of interest was measured by qPCR and Western Blotting. Cardiac remodeling will be evaluated by histology tests.ResultsWhen RAW264.7 macrophages were treated with palmitate (0.25 mM) for 24hr, expression level of Sectm1a was reduced by 46%; such reduction was further proved to be dose‐and time‐dependent of palmitate. Similarly, Sectm1a mRNA level decreased by 50% and 60% in bone marrow‐derived macrophages (BMDM) treated with palmitate (0.5 mM, 24hr) and T2D diabetic hearts, respectively. These data indicate that Sectm1a is associated with macrophage behavior in response to metabolic stress. To test whether macrophage polarization could be regulated by Sectm1a, we transfected macrophages with adenovirus encoding Sectm1a for 48hr or treated them with recombinant Sectm1a protein (40ng/ml) for 20hr, and observed macrophage transition from M1 to M2 phenotype, evidenced by significantly decreased M1 markers (i.e., iNOS) and increased M2 markers (i.e., Arg1). In addition, increased Sectm1a levels in macrophages suppressed the expression of chemokines (i.e., Ccl2 and Vcam1) and production of cytokines (i.e., TNFα, IL‐1β, and IL‐6). Interestingly, we observed similar results even after macrophages were treated with palmitate, indicating that Sectm1a could elicit protective effects against metabolic stress by enhancing M2 macrophage phenotype and subsequently resolving inflammation. Of importance, 1 month after STZ injection, Sectm1a‐deficient mice displayed exacerbated insulin resistance and cardiac dysfunction, both of which could be attributed to increased inflammation mediated by M1 macrophages. Furthermore, transplantation of Sectm1a‐engineered macrophages were able to reduce inflammation and relieve cardiac dysfunction in diabetic mice.ConclusionOur study demonstrates for the first time that Sectm1a could modulate macrophage polarization and suppress inflammatory response under diabetic conditions, leading to attenuation of diabetes‐induced cardiomyopathy.Support or Funding InformationNIH R01 GM‐112930, Albert J. Ryan FellowshipThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.