angiotensin-i and Diabetic-Cardiomyopathies

Renin-angiotensin system (RAS) is activated in diabetes. The rise of angiotension II (Ang II) stimulates the cardiac fibroblast proliferation and the alteration of collagen metabolism through AT1 receptor on cell surface, causing the myocardium interstitial and perivascular fibrosis, and the ventricular myocardium rigidity and diastolic function disturbance, leading to the clinical symptoms of diabetic cardiomyopathy (DCM). The main members of RAS including Ang II, Ang-(1-7), Ac-SDKP and ATR play the important role in the development of DCM. This article reviewed the interactions between RAS and endothelin (ET), reactive oxygen species (ROS), transforming growth factor-beta 1 (TGF-beta 1), nuclear factor-kappa b (NF-kappaB), signal transduction system and apoptosis in DCM.

Topics: Angiotensin I; Angiotensin II; Animals; Apoptosis; Diabetic Cardiomyopathies; Humans; NF-kappa B; Oligopeptides; Peptide Fragments; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Signal Transduction; Transforming Growth Factor beta1

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Benzimidazoles; Blood Pressure; Diabetic Cardiomyopathies; Male; Mice; Mice, Transgenic; Oxadiazoles; Oxidative Stress; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Signal Transduction

In diabetic patients, left ventricular (LV) remodeling is highly prevalent; however, little is known about the impact of diabetes on right ventricular (RV) structure and function. We recently found that overexpression of angiotensin (ANG)-converting enzyme 2 (ACE2), which metabolizes ANG-II to ANG-(1-7) and ANG-I to ANG-(1-9), may improve LV remodeling in diabetic cardiomyopathy (DCM). Here, we aimed to assess whether LV remodeling and dysfunction are paralleled by RV alterations and the effects of ANG-(1-7) on RV remodeling in DCM. After 12 wk of diabetes induced by a single intraperitoneal injection of streptozotocin, rats were treated with saline, ANG-(1-7), perindopril, ANG-(1-7) plus perindopril, ANG-(1-7) plus Mas receptor antagonist A779, or ANG-(1-7) plus ANG-II type 2 receptor antagonist PD123319 for 4 wk. RV remodeling in diabetic rats was indicated by fibrosis of the RV free wall in the absence of hypertrophy and apoptosis. Treatment with ANG-(1-7) prevented diabetes-induced RV fibrosis and dysfunction. ANG-(1-7) (800 ng·kg(-1)·min(-1)) was superior to perindopril in improving RV fibrosis. The major mechanisms involved a complex interaction of ANG-II type 2 and Mas receptors for subsequent downregulation of ACE expression and activity and ANG-II type 1 receptor expression, as well as upregulation of ACE2 expression and activity and the expression of ANG-II type 2 receptor and sarco(endo)plasmic reticulum Ca(2+)-ATPase. Thus RV fibrosis and dysfunction plays a central role in DCM, and ANG-(1-7) mitigates diabetes-induced RV alterations.

Topics: Angiotensin I; Animals; Blood Glucose; Cells, Cultured; Coculture Techniques; Collagen; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Cardiomyopathies; Fibrosis; Heart Ventricles; Lipids; Male; Oxidative Stress; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats, Wistar; Receptor, Angiotensin, Type 2; Receptors, G-Protein-Coupled; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Signal Transduction; Time Factors; Transforming Growth Factor beta1; Ventricular Dysfunction, Right; Ventricular Function, Right; Ventricular Remodeling

We recently found that overexpression of angiotensin (Ang)-converting enzyme 2, which metabolizes Ang-II to Ang-(1-7) and Ang-I to Ang-(1-9), may improve left ventricular remodeling in diabetic cardiomyopathy. Here we aimed to test whether chronic infusion of Ang-(1-7) can dose-dependently ameliorate left ventricular remodeling and function in a rat model of diabetic cardiomyopathy and whether the combination of Ang-(1-7) and Ang-converting enzyme inhibition may be superior to single therapy. Our results showed that Ang-(1-7) treatment dose-dependently ameliorated left ventricular remodeling and dysfunction in diabetic rats by attenuating myocardial fibrosis, myocardial hypertrophy and myocyte apoptosis via both the Mas receptor and angiotensin II type 2 receptor. Furthermore, combining Ang-(1-7) with perindopril provided additional cardioprotection relative to single therapy. Ang-(1-7) administration provides a novel and promising approach for treatment of diabetic cardiomyopathy.

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Apoptosis; Blood Glucose; Cardiomegaly; Cell Communication; Cell Differentiation; Cell Proliferation; Collagen; Diabetic Cardiomyopathies; Disease Models, Animal; Drug Therapy, Combination; Echocardiography; Fibroblasts; Fibrosis; Heart Ventricles; Hemodynamics; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Peptide Fragments; Peptidyl-Dipeptidase A; Perindopril; Phosphorylation; Rats; Receptors, Angiotensin; Transforming Growth Factor beta1; Ventricular Dysfunction, Left

The angiotensin-converting enzyme 2 and angiotensin-(1-7) (Ang 1-7)/MasR (Mas receptor) axis are emerging as a key pathway that can modulate the development of diabetic cardiomyopathy. We studied the effects of Ang 1-7 on diabetic cardiomyopathy in db/db diabetic mice to elucidate the therapeutic effects and mechanism of action.. Ang 1-7 was administered to 5-month-old male db/db mice for 28 days via implanted micro-osmotic pumps. Ang 1-7 treatment ameliorated myocardial hypertrophy and fibrosis with normalization of diastolic dysfunction assessed by pressure-volume loop analysis and echocardiography. The functional improvement by Ang 1-7 was accompanied by a reduction in myocardial lipid accumulation and systemic fat mass and inflammation and increased insulin-stimulated myocardial glucose oxidation. Increased myocardial protein kinase C levels and loss of phosphorylation of extracellular signal-regulated kinase 1/2 were prevented by Ang 1-7. Furthermore, Ang 1-7 treatment decreased cardiac triacylglycerol and ceramide levels in db/db mice, concomitantly with an increase in myocardial adipose triglyceride lipase expression. Changes in adipose triglyceride lipase expression correlated with increased SIRT1 (silent mating type information regulation 2 homolog 1) levels and deacetylation of FOXO1 (forkhead box O1).. We identified a novel beneficial effect of Ang 1-7 on diabetic cardiomyopathy that involved a reduction in cardiac hypertrophy and lipotoxicity, adipose inflammation, and an upregulation of adipose triglyceride lipase. Ang 1-7 completely rescued the diastolic dysfunction in the db/db model. Ang 1-7 represents a promising therapy for diabetic cardiomyopathy associated with type 2 diabetes mellitus.

Topics: Angiotensin I; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Diastole; Echocardiography, Doppler; Follow-Up Studies; Inflammation; Insulin Resistance; Lipids; Male; Mice; Mice, Inbred C57BL; Peptide Fragments; Vasodilator Agents; Ventricular Dysfunction, Left; Ventricular Function; Ventricular Pressure

This study was designed to investigate the effect of angiotensin (1-7), a Mas receptor agonist, and A-779, a Mas receptor antagonist, in rats with diabetic cardiomyopathy (DC).. Rats treated with a single injection of streptozotocin (50 mg/kg, intraperitoneal), developed DC after 8 weeks. The extent of DC was assessed by measuring the left ventricular weight/body weight (LVW/BW) ratio, absolute LVW, left ventricular developed pressure (LVDP), maximum change in left ventricular pressure over time (dp/dtmax), minimum change in left ventricular pressure over time (dp/dtmin), left ventricular (LV) protein content, LV collagen content, lipid profile, and serum nitrite/nitrate concentration. Test drug treatment was given from week 4 to week 8.. Angiotensin (1-7) treatment attenuated DC by significantly increasing LVDP, dp/dtmax, dp/dtmin, serum nitrite/nitrate concentration and significantly decreasing the LVW/BW ratio and LV collagen content. For the first time, this study has documented that endogenous angiotensin (1-7) regulates lipid profile in rats, and that treatment with angiotensin (1-7) significantly attenuates diabetes-induced changes in lipid profile. However, LV protein content and absolute LVW remain unaffected after treatment.. Angiotensin (1-7) significantly attenuates DC in rats because of vasodilatory, antiproliferative and anifibrotic properties but also because of a significant decrease in dyslipidemia, the major culprit for cardiac dysfunctions in diabetes.

Topics: Angiotensin I; Angiotensin II; Animals; Blood Glucose; Collagen; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Dyslipidemias; Fibrosis; Heart Ventricles; Hypertrophy, Left Ventricular; Lipids; Nitrates; Nitrites; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Time Factors; Ventricular Function, Left; Ventricular Pressure