Exendin-4 attenuates adverse cardiac remodelling in streptozocin-induced diabetes via specific actions on infiltrating macrophages

Abstract

In addition to its' established metabolic and cardioprotective effects, glucagon-like peptide-1 (GLP-1) reduces post-infarction heart failure via preferential actions on the extracellular matrix (ECM). Here, we investigated whether the GLP-1 mimetic, exendin-4, modulates cardiac remodelling in experimental diabetes by specifically targeting inflammatory/ECM pathways, which are characteristically dysregulated in this setting. Adult mice were subjected to streptozotocin (STZ) diabetes and infused with exendin-4/insulin/saline from 0 to 4 or 4–12 weeks. Exendin-4 and insulin improved metabolic parameters in diabetic mice after 12 weeks, but only exendin-4 reduced cardiac diastolic dysfunction and interstitial fibrosis in parallel with altered ECM gene expression. Whilst myocardial inflammation was not evident at 12 weeks, CD11b-F4/80++ macrophage infiltration at 4 weeks was increased and reduced by exendin-4, together with an improved cytokine profile. Notably, media collected from high glucose-treated macrophages induced cardiac fibroblast differentiation, which was prevented by exendin-4, whilst several cytokines/chemokines were differentially expressed/secreted by exendin-4-treated macrophages, some of which were modulated in STZ exendin-4-treated hearts. Our findings suggest that exendin-4 preferentially protects against ECM remodelling and diastolic dysfunction in experimental diabetes via glucose-dependent modulation of paracrine communication between infiltrating macrophages and resident fibroblasts, thereby indicating that cell-specific targeting of GLP-1 signalling may be a viable therapeutic strategy in this setting.Electronic supplementary materialThe online version of this article (doi:10.1007/s00395-015-0518-1) contains supplementary material, which is available to authorized users.

Glucagon‐like peptide‐1 ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via the PPARα pathway

“…Some studies have attributed the benefits of Ex‐4 on DCM to its effects on infiltrating macrophages, cardiac microvascular injury, and mitochondrial dysfunction (Tate et al., 2016; Wang et al., 2013; Wassef et al., 2017). However, the present study mainly focused on the effects of GLP‐1 on lipid regulation because, along with hyperglycemia, lipid accumulation and toxicity play key roles in DCM (Kusminski et al., 2009; Yang et al., 2007).…”

“…GLP‐1R agonists and DPP‐4 inhibitors have beneficial effects on the cardiovascular system (Ban et al., 2008; Noyan‐Ashraf et al., 2009; Timmers et al., 2009). Previous studies have shown that GLP‐1 and its analogs protected the heart against ischemia‐reperfusion injury and diabetes mellitus (Tate, Robinson, Green, McDermott & Grieve, 2016; Wang et al., 2013). They also protected isolated CMs from oxidative damage (Chang et al., 2013) and high‐glucose stress (Younce, Burmeister & Ayala, 2013).…”

4-Hydroxynonenal dependent alteration of TRPV1-mediated coronary microvascular signaling

“…The right jugular vein was visualized and cannulated for intravenous drug infusions. See Methods and Materials Section from DelloStritto et al, for complete description [25]. …”

“…Mice were infused with capsaicin (1–100 μg/kg), 4-HNE (4 mg/kg over 10 min), and non-targeted contrast. For complete description of methods, see Guarini et al [4] and DelloStritto et al [25]. …”

“…Having recently demonstrated that an enhanced oxidative environment (i.e. diabetic state) diminishes TRPV1 activity [25], the aim of our current study was to investigate the role of 4-HNE on TRPV1-mediated vascular signaling. Moreover, we aimed to further explore the physical interaction and PTM of TRPV1 by 4-HNE.…”