Mitchel Tate

Selective targeting of glucagon‐like peptide‐1 signalling as a novel therapeutic approach for cardiovascular disease in diabetes

Glucagon‐like peptide‐1 (GLP‐1) is an incretin hormone whose glucose‐dependent insulinotropic actions have been harnessed as a novel therapy for glycaemic control in type 2 diabetes. Although it has been known for some time that the GLP‐1 receptor is expressed in the CVS where it mediates important physiological actions, it is only recently that specific cardiovascular effects of GLP‐1 in the setting of diabetes have been described. GLP‐1 confers indirect benefits in cardiovascular disease (CVD) under both normal and hyperglycaemic conditions via reducing established risk factors, such as hypertension, dyslipidaemia and obesity, which are markedly increased in diabetes. Emerging evidence indicates that GLP‐1 also exerts direct effects on specific aspects of diabetic CVD, such as endothelial dysfunction, inflammation, angiogenesis and adverse cardiac remodelling. However, the majority of studies have employed experimental models of diabetic CVD and information on the effects of GLP‐1 in the clinical setting is limited, although several large‐scale trials are ongoing. It is clearly important to gain a detailed knowledge of the cardiovascular actions of GLP‐1 in diabetes given the large number of patients currently receiving GLP‐1‐based therapies. This review will therefore discuss current understanding of the effects of GLP‐1 on both cardiovascular risk factors in diabetes and direct actions on the heart and vasculature in this setting and the evidence implicating specific targeting of GLP‐1 as a novel therapy for CVD in diabetes.

Are targeted therapies for diabetic cardiomyopathy on the horizon

Diabetes increases the risk of heart failure approximately 2.5-fold, independent of coronary artery disease and other comorbidities. This process, termed diabetic cardiomyopathy, is characterized by initial impairment of left ventricular (LV) relaxation followed by LV contractile dysfunction. Post-mortem examination reveals that human diastolic dysfunction is closely associated with LV damage, including cardiomyocyte hypertrophy, apoptosis and fibrosis, with impaired coronary microvascular perfusion. The pathophysiological mechanisms underpinning the characteristic features of diabetic cardiomyopathy remain poorly understood, although multiple factors including altered lipid metabolism, mitochondrial dysfunction, oxidative stress, endoplasmic reticulum (ER) stress, inflammation, as well as epigenetic changes, are implicated. Despite a recent rise in research interrogating these mechanisms and an increased understanding of the clinical importance of diabetic cardiomyopathy, there remains a lack of specific treatment strategies. How the chronic metabolic disturbances observed in diabetes lead to structural and functional changes remains a pertinent question, and it is hoped that recent advances, particularly in the area of epigenetics, among others, may provide some answers. This review hence explores the temporal onset of the pathological features of diabetic cardiomyopathy, and their relative contribution to the resultant disease phenotype, as well as both current and potential therapeutic options. The emergence of glucose-optimizing agents, namely glucagon-like peptide-1 (GLP-1) agonists and sodium/glucose co-transporter (SGLT)2 inhibitors that confer benefits on cardiovascular outcomes, together with novel experimental approaches, highlight a new and exciting era in diabetes research, which is likely to result in major clinical impact.

Insulin replacement limits progression of diabetic cardiomyopathy in the low-dose streptozotocin-induced diabetic rat

Diabetic cardiomyopathy is a major contributor to the increasing burden of heart failure globally. Effective therapies remain elusive, in part due to the incomplete understanding of the mechanisms underlying diabetes-induced myocardial injury. The objective of this study was to assess the direct impact of insulin replacement on left ventricle structure and function in a rat model of diabetes. Male Sprague-Dawley rats were administered streptozotocin (55 mg/kg i.v.) or citrate vehicle and were followed for 8 weeks. A subset of diabetic rats were allocated to insulin replacement (6 IU/day insulin s.c.) for the final 4 weeks of the 8-week time period. Diabetes induced the characteristic systemic complications of diabetes (hyperglycaemia, polyuria, kidney hypertrophy) and was accompanied by marked left ventricle remodelling (cardiomyocyte hypertrophy, left ventricle collagen content) and diastolic dysfunction (transmitral E/A, left ventricle-dP/dt). Importantly, these systemic and cardiac impairments were ameliorated markedly following insulin replacement, and moreover, markers of the diabetic cardiomyopathy phenotype were significantly correlated with the extent of hyperglycaemia. In summary, these data suggest that poor glucose control directly contributes towards the underlying features of experimental diabetic cardiomyopathy, at least in the early stages, and that adequate replacement ameliorates this.

Gremlin1 plays a key role in kidney development and renal fibrosis

Gremlin1 (Grem1), an antagonist of bone morphogenetic proteins, plays a key role in embryogenesis. A highly specific temporospatial gradient of Grem1 and bone morphogenetic protein signaling is critical to normal lung, kidney, and limb development. Grem1 levels are increased in renal fibrotic conditions, including acute kidney injury, diabetic nephropathy, chronic allograft nephropathy, and immune glomerulonephritis. We demonstrate that a small number of grem1−/− whole body knockout mice on a mixed genetic background (8%) are viable, with a single, enlarged left kidney and grossly normal histology. The grem1−/− mice displayed mild renal dysfunction at 4 wk, which recovered by 16 wk. Tubular epithelial cell-specific targeted deletion of Grem1 (TEC-grem1-cKO) mice displayed a milder response in the acute injury and recovery phases of the folic acid model. Increases in indexes of kidney damage were smaller in TEC-grem1-cKO than wild-type mice. In the recovery phase of the folic acid model, associated with renal fibrosis, TEC-grem1-cKO mice displayed reduced histological damage and an attenuated fibrotic gene response compared with wild-type controls. Together, these data demonstrate that Grem1 expression in the tubular epithelial compartment plays a significant role in the fibrotic response to renal injury in vivo.

Oxidative Stress and NLRP3-Inflammasome Activity as Significant Drivers of Diabetic Cardiovascular Complications: Therapeutic Implications

It is now increasingly appreciated that inflammation is not limited to the control of pathogens by the host, but rather that sterile inflammation which occurs in the absence of viral or bacterial pathogens, accompanies numerous disease states, none more so than the complications that arise as a result of hyperglycaemia. Individuals with type 1 or type 2 diabetes mellitus (T1D, T2D) are at increased risk of developing cardiac and vascular complications. Glucose and blood pressure lowering therapies have not stopped the advance of these morbidities that often lead to fatal heart attacks and/or stroke. A unifying mechanism of hyperglycemia-induced cellular damage was initially proposed to link elevated blood glucose levels with oxidative stress and the dysregulation of metabolic pathways. Pre-clinical evidence has, in most cases, supported this notion. However, therapeutic strategies to lessen oxidative stress in clinical trials has not proved efficacious, most likely due to indiscriminate targeting by antioxidants such as vitamins. Recent evidence now suggests that oxidative stress is a major driver of inflammation and vice versa, with the latest findings suggesting not only a key role for inflammatory pathways underpinning metabolic and haemodynamic dysfunction in diabetes, but furthermore that these perturbations are driven by activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. This review will address these latest findings with an aim of highlighting the interconnectivity between oxidative stress, NLRP3 activation and inflammation as it pertains to cardiac and vascular injury sustained by diabetes. Current therapeutic strategies to lessen both oxidative stress and inflammation will be emphasized. This will be placed in the context of improving the burden of these diabetic complications.

Recent novel approaches to limit oxidative stress and inflammation in diabetic complications

Diabetes is considered a major burden on the healthcare system of Western and non‐Western societies with the disease reaching epidemic proportions globally. Diabetic patients are highly susceptible to developing micro‐ and macrovascular complications, which contribute significantly to morbidity and mortality rates. Over the past decade, a plethora of research has demonstrated that oxidative stress and inflammation are intricately linked and significant drivers of these diabetic complications. Thus, the focus now has been towards specific mechanism‐based strategies that can target both oxidative stress and inflammatory pathways to improve the outcome of disease burden. This review will focus on the mechanisms that drive these diabetic complications and the feasibility of emerging new therapies to combat oxidative stress and inflammation in the diabetic milieu.

Endogenous Annexin-A1 Regulates Haematopoietic Stem Cell Mobilisation and Inflammatory Response Post Myocardial Infarction in Mice In Vivo

Endogenous anti-inflammatory annexin-A1 (ANX-A1) plays an important role in preserving left ventricular (LV) viability and function after ischaemic insults in vitro, but its long-term cardioprotective actions in vivo are largely unknown. We tested the hypothesis that ANX-A1-deficiency exaggerates inflammation, haematopoietic stem progenitor cell (HSPC) activity and LV remodelling in response to myocardial ischaemia in vivo. Adult ANX-A1−/− mice subjected to coronary artery occlusion exhibited increased infarct size and LV macrophage content after 24–48 h reperfusion compared with wildtype (WT) counterparts. In addition, ANX-A1−/− mice exhibited greater expansion of HSPCs and altered pattern of HSPC mobilisation 8 days post-myocardial infarction, with increased circulating neutrophils and platelets, consistent with increased cardiac inflammation as a result of increased myeloid invading injured myocardium in response to MI. Furthermore, ANX-A1−/− mice exhibited significantly increased expression of LV pro-inflammatory and pro-fibrotic genes and collagen deposition after MI compared to WT counterparts. ANX-A1-deficiency increased cardiac necrosis, inflammation, hypertrophy and fibrosis following MI, accompanied by exaggerated HSPC activity and impaired macrophage phenotype. These findings suggest that endogenous ANX-A1 regulates mobilisation and differentiation of HSPCs. Limiting excessive monocyte/neutrophil production may limit LV damage in vivo. Our findings support further development of novel ANX-A1-based therapies to improve cardiac outcomes after MI.

GLUCAGON-LIKE PEPTIDE-1 PROTECTS AGAINST CARDIAC DYSFUNCTION AND EXTRACELLULAR MATRIX REMODELLING IN EXPERIMENTAL DIABETES

Glucagon-like peptide-1 (GLP-1) is an insulin-releasing hormone with established cardiovascular actions. Here, we investigated effects of exendin-4, a stable GLP-1 mimetic, on cardiac remodelling in experimental diabetes. Male C57BL/6J mice were injected with streptozotocin (STZ; 50 mg/kg/day for 5 days) or vehicle control prior to starting infusion with exendin-4 (25 nmol/kg/day) at 4 weeks. Continuous treatment with exendin-4 for 8 weeks had no effect on body weight but reduced blood glucose in STZ-treated animals (HbA1c: control 6.6±0.3 vs STZ saline 11.8±1.1, p<0.01; exendin-4 9.4±0.9 vs STZ exendin-4 6.5±0.3%, p=NS; n=4–9). Echocardiography indicated that systolic function, assessed by fractional shortening, was similar between groups. However, diastolic dysfunction observed after STZ treatment was attenuated by exendin-4 (mitral valve E/A: STZ saline 1.17±0.04 vs STZ exendin-4 1.51±0.09, p<0.05; n=3–8). Interestingly, these functional effects were associated with an improved pro-fibrotic gene expression profile, as assessed by real-time RT-PCR. For example, expression of procollagen I mRNA was reduced in STZ animals after exendin-4 treatment (STZ saline 4.32±0.27 vs STZ exendin-4 3.02±0.37 arbitrary units, p<0.05; n=5–8), and similar patterns were observed for procollagen III and fibronectin. Furthermore, differential STZ-induced effects on mRNA expression of matrix metalloproteinase-2 (MMP-2) (control 7.30±0.46 vs STZ saline 9.21±0.49, p<0.05; exendin-4 6.50±0.11 vs STZ exendin-4 7.70±0.45 arbitrary units, p=NS; n=5–7) and MMP-9 (STZ saline 1.70±0.35 vs STZ exendin-4 3.84±0.63 arbitrary units, p<0.05; n=5–8) were inhibited by exendin-4. These data indicate that GLP-1 protects against adverse cardiac remodelling in diabetes via modulation of the extracellular matrix, although the underlying mechanisms remain unclear.

Author Correction: Endogenous Annexin-A1 Regulates Haematopoietic Stem Cell Mobilisation and Inflammatory Response Post Myocardial Infarction in Mice In Vivo

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.