Obesity Distinctly Influences Cardiac Function and Molecular Responses to Ischemia‐Reperfusion and GLP‐1 Receptor Agonism

Field: Medicine (Health Sciences)

This study tested the hypothesis that obesity distinctly alters the microRNA (miR) transcriptome and proteome in the myocardium, and that these changes are associated with alterations in left ventricular pressure and volume in response to ischemia‐reperfusion (I/R) injury and to glucagon like peptide‐1 (GLP‐1) receptor activation. Ossabaw swine were fed either a normal or high calorie, obesogenic diet for 6 months. Following this period, swine received 24 hours of either the GLP‐1 mimetic exendin‐4 (EX‐4) (30 fmol/kg/min) or saline‐vehicle. Left ventricular pressure and volume were subsequently assessed using an admittance pressure‐volume catheter in anesthetized, open‐chest swine. Recordings were obtained under baseline conditions, during 30‐min circumflex coronary artery occlusion, and for 2 hours following coronary reperfusion. Cardiac biopsies were obtained from normally perfused and ischemia‐reperfusion territories following completion of the reperfusion period. Biopsies were used for Affymetrix 3.0 mIR microarray, and protein mass spectrometry. Obesity was associated with systematic alterations of expression of cardiac miRs relating to cardiac metabolism, hypertrophy, and cell death, including miR‐15, miR‐27, miR130, miR‐181, and let‐7. These effects were modified differently by EX‐4 treatment in lean vs obese swine. The abundance of key cardiac regulatory and functional proteins also differed in lean vs obese hearts, most notably proteins related to myocardial calcium handling (SERCA2a, histidine‐rich Ca 2+ binding protein) and myocardial structure and function (titin). These molecular changes were associated with significant differences in physiologic response to regional I/R in obese vs lean hearts. In lean swine I/R produced marked reductions in indices of global contractile function, namely significant reductions in systolic pressure, end‐diastolic volume, stroke volume, and ejection fraction. These indices of cardiac function were significantly higher in obese vs lean hearts at baseline, were relatively maintained throughout I/R, and were accompanied by a rightward shift in pressure‐volume relationship. EX‐4 administration significantly increased peak systolic pressure and tended to increase end‐diastolic volume in lean swine following ischemia‐reperfusion. EX‐4 did not affect blood pressure in obese swine but significantly reduced end‐diastolic volume following the reperfusion period. Taken together, these findings suggest specific miR and proteomic programmatic differences that may contribute to distinct differences in functional cardiac responses to ischemia‐reperfusion injury and pharmacologic activation of GLP‐1 signaling in the setting of obesity. Further studies are needed to distinguish which changes are causal vs secondary to the observed physiologic effects. Support or Funding Information This work was supported by a National Institutes of Health grant, HL117620 (J. Tune and K. Mather, PI). Dr. Goodwill was supported by American Heart Association 13POST1681001813 (A. Goodwill, PI). Mr. Conteh was supported by National Institutes of Health HL117620‐S1 (J. Tune and K. Mather, PI). Mr. Sassoon and Ms. Noblet were supported by grant number TL1 TR000162 (A. Shekhar, PI) from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award.