Interaction of diabetes and ACE2 in the pathogenesis of cardiovascular disease in experimental diabetes

Tikellis, Chris; Pickering, Raelene; Tsorotes, Despina; Du, Xiao Jun; Kiriazis, Helen; Nguyen‐Huu, Thu‐Phuc; Head, Geoffrey A.; Cooper, Mark E.; Thomas, Merlin C.

doi:10.1042/cs20110668

Cited by 53 publications

(38 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…135 Further studies have validated our findings for this essential role of ACE2 in diabetic cardiomyopathy. 136, 138–140, 144 We also identified beneficial effects of Ang 1–7 in type 2 diabetic cardiomyopathy. By reducing cardiac hypertrophy, lipotoxicity, and adipose inflammation, in combination with increased adipose triglyceride lipase, Ang 1–7 completely rescued diastolic dysfunction in the db/db type 2 diabetic murine model.…”

Section: Role Of Ace2/ang 1–7 In Hfmentioning

confidence: 73%

Role of the ACE2/Angiotensin 1–7 Axis of the Renin–Angiotensin System in Heart Failure

Patel

Zhong

Grant

et al. 2016

Circulation Research

740

704

View full text Add to dashboard Cite

Heart failure remains the most common cause of death and disability, and a major economic burden, in industrialized nations. Physiological, pharmacological, and clinical studies have demonstrated that activation of the renin-angiotensin system is a key mediator of heart failure progression. Angiotensin converting enzyme 2 (ACE2), a homologue of ACE, is a monocarboxypeptidase that converts angiotensin II (Ang II) into angiotensin 1–7 (Ang 1–7) which, by virtue of its actions on the Mas receptor, opposes the molecular and cellular effects of Ang II. ACE2 is widely expressed in cardiomyocytes, cardiofibroblasts, and coronary endothelial cells. Recent preclinical translational studies confirmed a critical counter-regulatory role of ACE2/Ang 1–7 axis on the activated renin-angiotensin system that results in heart failure with preserved ejection fraction. While loss of ACE2 enhances susceptibility to heart failure, increasing ACE2 level prevents and reverses the heart failure phenotype. ACE2 and Ang 1–7 have emerged as a key protective pathway against heart failure with reduced and preserved ejection fraction. Recombinant human ACE2 has been tested in phase I and II clinical trials without adverse effects while lowering and increasing plasma Ang II and Ang 1–7 levels, respectively. This review discusses the transcriptional and post-transcriptional regulation of ACE2 and the role of the ACE2/Ang 1–7 axis in cardiac physiology and in the pathophysiology of heart failure. The pharmacological and therapeutic potential of enhancing ACE2/Ang 1–7 action as a novel therapy for heart failure is highlighted.

show abstract

Section: Role Of Ace2/ang 1–7 In Hfmentioning

confidence: 73%

Role of the ACE2/Angiotensin 1–7 Axis of the Renin–Angiotensin System in Heart Failure

Patel

Zhong

Grant

et al. 2016

Circulation Research

740

704

View full text Add to dashboard Cite

show abstract

“…There is controversy about the development of hypertension in db/db mice as some studies reported an increase [30], [31], while others reported no change in blood pressure [19], [32]. The hypertension observed by some investigators has been attributed to increased plasma AngII levels secondary to changes in angiotensin converting enzyme [31] and angiotensin converting enzyme-2 [33] activity in diabetic animals. In the present study blood pressure was not elevated in awake 14–18 wks old diabetic db/db mice as compared to age-matched non-diabetic db/+ controls.…”

Section: Discussionmentioning

confidence: 99%

Hypertension Is a Conditional Factor for the Development of Cardiac Hypertrophy in Type 2 Diabetic Mice

et al. 2014

View full text Add to dashboard Cite

BackgroundType 2 diabetes is frequently associated with co-morbidities, including hypertension. Here we investigated if hypertension is a critical factor in myocardial remodeling and the development of cardiac dysfunction in type 2 diabetic db/db mice.MethodsThereto, 14-wks-old male db/db mice and non-diabetic db/+ mice received vehicle or angiotensin II (AngII) for 4 wks to induce mild hypertension (n = 9–10 per group). Left ventricular (LV) function was assessed by serial echocardiography and during a dobutamine stress test. LV tissue was subjected to molecular and (immuno)histochemical analysis to assess effects on hypertrophy, fibrosis and inflammation.ResultsVehicle-treated diabetic mice neither displayed marked myocardial structural remodeling nor cardiac dysfunction. AngII-treatment did not affect body weight and fasting glucose levels, and induced a comparable increase in blood pressure in diabetic and control mice. Nonetheless, AngII-induced LV hypertrophy was significantly more pronounced in diabetic than in control mice as assessed by LV mass (increase +51% and +34%, respectively, p<0.01) and cardiomyocyte size (+53% and +31%, p<0.001). This was associated with enhanced LV mRNA expression of markers of hypertrophy and fibrosis and reduced activation of AMP-activated protein kinase (AMPK), while accumulation of Advanced Glycation End products (AGEs) and the expression levels of markers of inflammation were not altered. Moreover, AngII-treatment reduced LV fractional shortening and contractility in diabetic mice, but not in control mice.ConclusionsCollectively, the present findings indicate that type 2 diabetes in its early stage is not yet associated with adverse cardiac structural changes, but already renders the heart more susceptible to hypertension-induced hypertrophic remodeling.

show abstract

“…They found that treatment of STZ-induced Type 1 diabetic rats with XNT, an ACE2 activator, resulted in increased ACE2/ACE mRNA and protein as well activity levels, along with decreased AT 1 R expression, which was associated with inhibition of ERK1/2 (extracellular-signal-regulated kinases 1/2), AMPKα (AMP-activated protein kinase α) and AMPKβ expression. Tikellis et al [91] found decreased myocardial ACE2 expression and Ang-(1-7) levels with increased circulating AngII levels in STZ-treated Type 1 diabetic mice, resulting in thinning of the LV wall and mild ventricular dilation associated with increased apoptosis and myocyte hypertrophy. Interestingly, DX-600 as well as A779 treatment in STZ-treated rats augmented the Type-1-diabetes-induced NADPH oxidase activation in cardiac tissue, resulting in ROS-production-induced cardiac dysfunction, where these effects were reversed by pretreatment with captopril or losartan [88].…”

Section: Heart Diseasementioning

confidence: 99%

“…XNT also inhibited STZ-induced hyperglycaemia [86] and improved autonomic function [87], resulting in improved cardiac function, decreased blood pressure and cardiac fibrosis. In contrast, at the same time the major phenotypic differences between ACE2KO and WT (wild-type) mice with respect to blood pressure and cardiac hypertrophy were eliminated following the induction of diabetes [91]. Tikellis et al [91] found decreased myocardial ACE2 expression and Ang-(1-7) levels with increased circulating AngII levels in STZ-treated Type 1 diabetic mice, resulting in thinning of the LV wall and mild ventricular dilation associated with increased apoptosis and myocyte hypertrophy.…”

Section: Heart Diseasementioning

confidence: 99%

Role of angiotensin-converting enzyme 2 (ACE2) in diabetic cardiovascular complications

2013

View full text Add to dashboard Cite

Diabetes mellitus results in severe cardiovascular complications, and heart disease and failure remain the major causes of death in patients with diabetes. Given the increasing global tide of obesity and diabetes, the clinical burden of diabetes-induced cardiovascular disease is reaching epidemic proportions. Therefore urgent actions are needed to stem the tide of diabetes which entails new prevention and treatment tools. Clinical and pharmacological studies have demonstrated that AngII (angiotensin II), the major effector peptide of the RAS (renin-angiotensin system), is a critical promoter of insulin resistance and diabetes mellitus. The role of RAS and AngII has been implicated in the progression of diabetic cardiovascular complications and AT1R (AngII type 1 receptor) blockers and ACE (angiotensin-converting enzyme) inhibitors have shown clinical benefits. ACE2, the recently discovered homologue of ACE, is a monocarboxypeptidase which converts AngII into Ang-(1-7) [angiotensin-(1-7)] which, by virtue of its actions on the MasR (Mas receptor), opposes the effects of AngII. In animal models of diabetes, an early increase in ACE2 expression and activity occurs, whereas ACE2 mRNA and protein levels have been found to decrease in older STZ (streptozotocin)-induced diabetic rats. Using the Akita mouse model of Type 1 diabetes, we have recently shown that loss of ACE2 disrupts the balance of the RAS in a diabetic state and leads to AngII/AT1R-dependent systolic dysfunction and impaired vascular function. In the present review, we will discuss the role of the RAS in the pathophysiology and treatment of diabetes and its complications with particular emphasis on potential benefits of the ACE2/Ang-(1-7)/MasR axis activation.

show abstract

Interaction of diabetes and ACE2 in the pathogenesis of cardiovascular disease in experimental diabetes

Cited by 53 publications

References 40 publications

Role of the ACE2/Angiotensin 1–7 Axis of the Renin–Angiotensin System in Heart Failure

Role of the ACE2/Angiotensin 1–7 Axis of the Renin–Angiotensin System in Heart Failure

Hypertension Is a Conditional Factor for the Development of Cardiac Hypertrophy in Type 2 Diabetic Mice

Role of angiotensin-converting enzyme 2 (ACE2) in diabetic cardiovascular complications

Contact Info

Product

Resources

About