Glutamine metabolism improves cardiac function after myocardial infarction independent of macrophage polarization

Abstract

During myocardial infarction (MI), macrophages (MØ) infiltrate the ischemic left ventricle (LV) and mediate cardiac remodeling and healing. Metabolic shifts in the LV and infiltrating MØs is a hallmark of the response to injury. Glutamine is a major metabolic fuel for cardiac muscle and MØs. However, the role of GLN metabolism in the remodeling heart after MI is not well understood. We used a model of permanent coronary artery ligation in adult male C57BL/6J mice to assess GLN metabolism in extracted cardiac MØs at post-MI days (D) 1, 3, and 7. Using untargeted metabolomics, we found time-dependent changes in metabolites related to GLN and glutamate (GLU) metabolism in cardiac MØs (p=6E-4). GLN levels were significantly increased at day 3, while GLU was decreased at day 7, and the GLN/GLU ratio was higher at both D3 and 7 compared to D1 post-MI. Using Seahorse extracellular flux analysis, GLN consumption in MØs was increased on D1 and 3. In the remote area of the heart (RA), genes for GLN-metabolizing enzymes (Glud1, Got1, Gpt1) were decreased at D3 and 7, indicating a loss of GLN metabolism. We then administered GLN (1 g/kg body weight, i.p.) daily post-MI for up to D3 or 7. Compared to vehicle, GLN administration increased ejection fraction at D3 (1.2-fold increase) and 7 post-MI (1.6-fold increase), and attenuated anterior and posterior wall thinning at D7 by 1.6-fold and 1.3-fold, respectively. GLN also restored expression of genes associated with GLN metabolism (Gls1, Glul, Got1, Gpt1, Glud1) in the RA, as well as glucose oxidation (Pdha1). GLN also restored Myh6 expression and attenuated Myh7 expression, indicating favorable expression of myosin heavy chains. However, GLN did not affect cardiac MØ phenotype, as assessed by flow cytometry and cytokine mRNA levels (Il1b, Tnf, Il6, Ccl2, Il18, and Il10). We then blocked GLN metabolism by administering BPTES (12.5 mg/kg daily i.p. in corn oil) to mice for 3 days post-MI. BPTES exacerbated anterior wall thinning (1.4-fold decrease) and further decreased EF (1.4-fold) after MI, and also increased expression of Myh7 in the RA. However, BPTES did not affect MØ phenotypes. In conclusion, dysregulation of GLN metabolism is a hallmark of post-MI cardiac remodeling, and enhancing GLN metabolism may improve cardiac function, but may not be effective for reducing MØ-mediated inflammation post-MI. Funding: NIDDK 1R01121411, P20GM104357, U54GM115428, AHA856365 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.