Cardioprotective Effects Mediated by Angiotensin II Type 1 Receptor Blockade and Enhancing Angiotensin 1-7 in Experimental Heart Failure in Angiotensin-Converting Enzyme 2–Null Mice

Abstract

Abstract-Loss of angiotensin (Ang)-converting enzyme 2 (ACE2) and inability to metabolize Ang II to Ang 1-7 perpetuate the actions of Ang II after biomechanical stress and exacerbate early adverse myocardial remodeling. Ang receptor blockers are known to antagonize the effect of Ang II by blocking Ang II type 1 receptor (AT 1 R) and also by upregulating the ACE2 expression. We directly compare the benefits of AT 1 R blockade versus enhancing Ang 1-7 action in pressure-overload-induced heart failure in ACE2 knockout mice. AT 1 R blockade and Ang 1-7 both resulted in marked recovery of systolic dysfunction in pressure-overloaded ACE2-null mice. Similarly, both therapies attenuated the increase in NADPH oxidase activation by downregulating the expression of Nox2 and p47 phox subunits and also by limiting the p47 phox phosphorylation. Biomechanical stress-induced increase in protein kinase C-␣ expression and phosphorylation of extracellular signal-regulated kinase 1/2, signal transducer and activator of transcription 3, Akt, and glycogen synthase kinase 3␤ were normalized by irbesartan and Ang 1-7. Ang receptor blocker and Ang 1-7 effectively reduced matrix metalloproteinase 2 activation and matrix metalloproteinase 9 levels. Ang II-mediated cellular effects in cultured adult cardiomyocytes and cardiofibrolasts isolated from pressure-overloaded ACE2-null hearts were inhibited to similar degree by AT 1 R blockade and stimulation with Ang 1-7. Thus, treatment with the AT 1 R blocker irbesartan and Ang 1-7 prevented the cardiac hypertrophy and improved cardiac remodeling in pressure-overloaded ACE2-null mice by suppressing NADPH oxidase and normalizing pathological signaling pathways. Key Words: renin-angiotensin system Ⅲ angiotensin 1-7 Ⅲ angiotensin-converting enzyme 2 Ⅲ NADPH oxidase Ⅲ AT 1 receptor Ⅲ heart failure Ⅲ signaling S everal lines of experimental and clinical evidence implicate a key role for the renin-angiotensin system in the pathophysiology of a number of cardiovascular diseases, such as myocardial infarction, hypertension, and heart failure. 1,2Angiotensin II (Ang II), acting via the Ang II type 1 receptor (AT 1 R) and Ang II type 2 receptor, modulates production of reactive oxygen species (ROS), impairing myocardial contractility and extracellular matrix remodeling, thereby negatively impacting on heart function.3 Angiotensin-converting enzyme 2 (ACE2), a homologue of angiotensin-converting enzyme, is a monocarboxypeptidase that metabolizes Ang II to yield angiotensin 1-7 (Ang 1-7) and lowers the Ang II/Ang 1-7 ratio.4-9 Ang II receptor blockers that selectively antagonize the AT 1 R became a valid alternative approach to interfere with the renin-angiotensin system axis and also upregulates ACE2, resulting in the generation of Ang 1-7. 10,11 Ang 1-7 acts on the Mas receptor and plays an important role in counteracting the actions of Ang II. 12-18Ang II-mediated oxidative stress, cardiac hypertrophy, contractile dysfunction, and fibrosis are exacerbated in ACE2-deficient mice, 5,7 whereas recombinant ...

Angiotensin-(1–7) Modulates Renal Vascular Resistance Through Inhibition of p38 Mitogen-Activated Protein Kinase in Apolipoprotein E–Deficient Mice

“…24 Recently, it has been acknowledged that Ang(1-7) plays an important role in the control of ROS level in the renal vasculature and affects p38 MAPK signaling in pathophysiological conditions. 24,[42][43][44] For instance, chronic Ang(1-7) treatment improved endothelial dysfunction and attenuated the progression of atherosclerosis in apoE(−/−) mice by reducing ROS production. 24,25,33 In contrast, ACE2 deficiency causes a marked increase in oxidative stress, which has been attributed to the diminished generation of Ang (1-7) by ACE2 deficiency as a counter regulatory mechanism to Ang II.…”

Molecular Biology of Atherosclerosis

“…STAT3 may also be activated by JAK2 (1394). A reduction of early atherosclerotic lesions was seen in fat fed mice with endothelial cell-specific STAT3 KO (610).…”

Angiotensin 1–7 Ameliorates Diabetic Cardiomyopathy and Diastolic Dysfunction in db/db Mice by Reducing Lipotoxicity and Inflammation

“…The myocardial level of SERCA2 and phospholamban was Furthermore, we hypothesized that Ang 1-7 treatment ameliorates reactive oxygen species-derived damage in hearts from db/db mice because lipotoxicity triggers oxidative stress and Ang 1-7 reduces NADPH-stimulated superoxide production. [33][34][35] Superoxide levels were increased in db/db hearts, driven by NADPH oxidase activity, leading to increased nitrotyrosine levels (Figure 7A and 7C; Figure IV in the Data Supplement). Ang 1-7 treatment prevented reactive oxygen species production in db/db hearts in association with lowered NADPH oxidase activity and nitrotyrosine levels (Figure 7A-7C; Figure IV in the Data Supplement).…”