Interleukin‐33 alleviates diabetic cardiomyopathy through regulation of endoplasmic reticulum stress and autophagy via insulin‐like growth factor‐binding protein 3

Abstract

Prolonged endoplasmic reticulum (ER) stress is the key driving force behind diabetic cardiomyopathy (DCM). Autophagy is extensively implicated in adaptive mechanisms for cell survival. Interleukin-33 (IL-33) is known to be a potent cardiac protector, but its roles in DCM, ER stress, and autophagy are currently unknown. We aimed to explore the effects of IL-33 on DCM and characterize the roles that ER stress and autophagy play in DCM. The effects of IL-33 on DCM, ER stress, and autophagy were characterized both in db/db mice and in palmitic acid (PA)-treated cardiomyocytes. The manipulators of ER stress and autophagy were used to clarify their roles in DCM remittance conferred by IL-33. Gene expression analysis was used to identify IL-33-dependent regulators of ER stress and autophagy. Both db/db mice and PA-treated cells presented with enhanced levels of ER stress, apoptosis, and lipid deposition, as well as impaired autophagy, all of which could be reversed by IL-33. Treatment with IL-33 improved the cardiac diastolic function of diabetic mice. Nonselective autophagy inhibitors, such as 3-methyladenine (3-MA) or wortmannin, abolished the protective effects of IL-33, resulting in an increase in both ER stress and apoptosis. Strikingly, insulin-like growth factor-binding protein 3 (IGFBP3) was identified as the gene most significantly differentially expressed between IL-33 and control groups. Knockdown of IGFBP3 expression, similar to the effect of nonselective autophagy inhibitors, resulted in high levels of ER stress, impaired autophagy, and apoptosis that were not rescued upon treatment with IL-33. IL-33 abates DCM by alleviating ER stress and promoting autophagy. IGFBP3 is essential for IL-33-induced ER stress resolution and autophagic enhancement during DCM.

Ketogenic Diet Suppressed T‐Regulatory Cells and Promoted Cardiac Fibrosis via Reducing Mitochondria‐Associated Membranes and Inhibiting Mitochondrial Function

“…P values were derived either from the t-test (a, d) or the ANOVA followed by SNK for multiple comparisons (b, c, e-h). 9 Oxidative Medicine and Cellular Longevity without concurrent systolic defects [19]. However, the abovementioned study showed a significant reduction of LVEF in db/db mice [4], which implied a late stage of DCM or other coexistent causes of cardiac insults.…”

“…Male C57BLKsJ-db/db mice were used to establish the spontaneous T2DM and DCM as our previous report [19]. Age-matched male C57BLKsJ-m/m mice were used as the control [19]. Mice were kept in a 12 h light/dark cycle with free access to chow and water.…”

“…Animals were anesthetized as mentioned above. Left ventricular ejection function (LVEF) and left ventricular end diastolic dimension (LVEDd) were measured by the Visual Sonics Echo System (Vevo2100, VisualSonics, Toronto, Canada) and MicroScan Transducer (MS-400, 30 MHz, VisualSonics, Toronto, Canada) [19].…”

“…The membrane ST2 (ST2L) mediates the biological effects of IL-33 while the soluble ST2 (sST2) acts as the decoy receptor that restricts the effects of IL-33 [18]. We recently demonstrated that interleukin-33 (IL-33) protected diabetic mice from DCM and reduced cardiac fibrosis [19]. However, the role of changes of endogenous IL-33/ST2L signaling and their potential roles in Tregs and KD-treated diabetes are unknown.…”

Vildagliptin Attenuates Myocardial Dysfunction and Restores Autophagy via miR-21/SPRY1/ERK in Diabetic Mice Heart

“…However, studies have found that the confounding effects of the classical risk factors that coexist in diabetes, such as hyperglycemia, insulin resistance, hyperlipidemia, metabolic disturbances, and neurohormonal activation, combined with other risk factors, may promote DCM progression. PA-treated H9c2 cells presented with enhanced levels of ER stress, apoptosis, and lipid deposition, as well as impaired autophagy ( Wu et al, 2020 ). Therefore, to better simulate T2DM, we will maintain the myocytes in “diabetic like” medium of insulin-high glucose ( Davidoff and Ren, 1997 ) or PA-high glucose ( Hu et al, 2019 ) to study the pathological mechanisms in further studies.…”