Posts Tagged: angiotensin II

Multifunctional Role of Chymase in Acute and Chronic Tissue Injury and Remodeling

Multifunctional Role of Chymase in Acute and Chronic Tissue Injury and Remodeling

Louis J. Dell’Italia, James F. Collawn, Carlos M. Ferrario

Evidence from human pathology and preclinical animal models supports the important role for chymase in cardiovascular stress. Upper left, Demonstrates a cross-section of a human renal artery with marked increase in chymase (brown) extending from the endothelium to adventitia in a patient with diabetes mellitus (reprinted from Koka et al60 with permission. Copyright ©2006, Wolters Kluwer Health). Center and upper right, Cartoons demonstrate the potential role of chymase in attenuating ischemia/reperfusion injury and promoting stabilization of the vulnerable atherosclerotic plaque (reprinted from Bentzon et al249 with permission. Copyright ©2014, Wolters Kluwer Health). Bottom right, Demonstrate the marked increase in left ventricular (LV) volume and LV wall thinning in a patient with chronic mitral regurgitation (MR; right) compared with a normal subject (left; reprinted from Zheng et al250 with permission. Copyright ©2014, Wolters Kluwer Health). Bottom left, Demonstrates the increase in LV volume and apical wall thinning in a patient 6 mo after an antero-apical myocardial infarction (MI; right) compared with 3 d after MI (left; reprinted from Foster et al251 with permission. Copyright ©1998, Elsevier). Targeting the multifunctional roles of chymase (Figure 2) in each of these conditions by chymase inhibition will complement conventional renin–angiotensin system (RAS) blockade in promoting better outcomes and tissue protection. [Powerpoint File]

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

Vaibhav B. Patel, Jiu-Chang Zhong, Maria B. Grant, Gavin Y. Oudit

Enzymatic cascade of the renin–angiotensin system (RAS), key receptor systems, and the biological effects mediated by angiotensin II (Ang II) and Ang 1–7. A, The RAS cascade showing the angiotensin peptide metabolic pathway. Angiotensinogen, as the starting substrate, is cleaved by renin to Ang I. Ang I is cleaved by angiotensin-converting enzyme (ACE) to Ang II, which is cleaved by ACE2 to Ang 1–7. Ang II acts on AT1 and AT2 receptors. Ang 1–7 acts on Mas receptors and counterbalances the Ang II/Ang II type 1 receptor (AT1R) actions. B, Decreased ACE2 shifts the balance in the RAS to the Ang II/AT1R axis, resulting in disease progression. Increased ACE2 (by rhACE2, gene delivery, or ACE2 activators) shifts the balance to the Ang 1–7/MasR axis, leading to protection from disease. APA indicates aminopeptidase A; PCP, prolyl carboxypeptidase; and rhACE2, recombinant human ACE2. [Powerpoint File]

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

Vaibhav B. Patel, Jiu-Chang Zhong, Maria B. Grant, Gavin Y. Oudit

Transcriptional, post-transcriptional, and post-translational regulation of angiotensin-converting enzyme 2 (ACE2). ACE2 expression is transcriptionally regulated by energy stress and activation of adenosine monophosphate kinase (AMPK) via sirtuin 1 (SIRT1), which binds to the promoter region and facilitates ACE2 mRNA expression. Similarly, apelin binds to the promoter region of ACE2 and enhances its expression. ACE2 mRNA is subject to post-transcriptional regulation by miR-421, which regulates protein expression. Angiotensin II (Ang II), the main effector peptide of the renin–angiotensin system, is produced by ACE and chymase in the heart and other tissues. ACE2, a monocarboxypeptidase, degrades Ang II into a heptapetide, Ang 1–7. Ang II, via its action on Ang II type 1 receptor (AT1R), promotes nicotinamide adenine dinucleotide phosphate oxidase 2 (Nox2)–dependent reactive oxygen species (ROS) formation. This leads to phosphorylation and activation of p38-mitogen-activated protein kinase (MAPK) and ultimately results in TACE phosphorylation (Thr735) and activation. Activated tumor necrosis factor-α–converting enzyme (TACE) proteolytically cleaves ACE2 and releases the active ACE2 ectodomain. AICAR indicates 5-amino-4-imidazolecarboxamide riboside; MasR, Mas receptor; and PKC, protein kinase C. [Powerpoint File]

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

Vaibhav B. Patel, Jiu-Chang Zhong, Maria B. Grant, Gavin Y. Oudit

Cardiac effects of the angiotensin II (Ang II)/Ang II type 1 receptor (AT1R) axis and counter-regulation by the angiotensin-converting enzyme 2 (ACE2)/Ang 1–7/Mas receptor (MasR axis). ACE-mediated generation of Ang II results in activation of various signaling pathways in cardiomyocytes, cardiac fibroblasts, and endothelial cells, resulting in adverse cardiac remodeling and cardiac dysfunction. Activation of the ACE2/Ang 1–7/MasR axis counter-regulates Ang II/AT1R-mediated effects and also stimulates cardiac contractility mediated by the phosphatidylinositol 3-kinase (PI3K)–Akt–endothelial nitric oxide synthase (eNOS) pathway. ARB indicates AT1R blocker; cGMP, cyclic guanosine monophosphate; DAG, diacyl glycerol; ECM, extracellular matrix; ERK, extracellular signal–regulated kinase; IP3, inositol triphosphate; JNK, c-Jun N-terminal kinases; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; MMP, matrix metalloproteinase; Nox2, nicotinamide adenine dinucleotide phosphate oxidase 2; PKC, protein kinase C; PLC, phospholipase C; and SMA, smooth muscle actin. [Powerpoint File]

Inflammation, Immunity, and Hypertensive End-Organ Damage

Inflammation, Immunity, and Hypertensive End-Organ Damage

William G. McMaster, Annet Kirabo, Meena S. Madhur, David G. Harrison

T cell activation by isoketal protein modification. Hypertension induces production of reactive oxygen species (ROS) in dendritic cells (DCs), leading to oxidation of arachidonic acid and formation of gamma ketoaldehydes or isoketals. Isoketals rapidly ligate to protein lysines in the DC, forming proteins that are recognized as nonself. Peptides from these are presented to T cells, leading to T cell proliferation. Isoketal formation also promotes DC production of cytokines, including IL-1β, IL-6, and IL-23, which polarize T cells to produce specific cytokines. IFN indicates interferon; IL, interleukin; MHC, major histocompatibility complexes; and TCR, T cell receptor. [Powerpoint File]

Inflammation, Immunity, and Hypertensive End-Organ Damage

Inflammation, Immunity, and Hypertensive End-Organ Damage

William G. McMaster, Annet Kirabo, Meena S. Madhur, David G. Harrison

Cytokines and end-organ dysfunction in hypertension. A, In vessels, T cells infiltrate the adventitia and perivascular fat through the vasa vasorum. T cell-derived interleukin (IL)-17A acts on smooth muscle cells and adventitial fibroblasts to increase endothelial nitric oxide synthase (eNOS) phosphorylation, reactive oxygen species (ROS) production, collagen synthesis, and chemokine production, leading to a decrease in bioavailable nitric oxide (NO) and impaired vasodilation, increased vascular stiffness, and increased recruitment of immune cells, propagating the inflammatory response. These effects result in vascular dysfunction. B, In the renal medulla and cortex, activated T cells produce cytokines, such as IL-6 and interferon (IFN)γ that stimulate production of angiotensinogen. Angiotensinogen is converted to angiotensin I (Ang I) by intrarenal renin and subsequently to angiotensin II (Ang II) by intrarenal angiotensin-converting enzyme. Angiotensin II upregulates and stimulates transport channels in the proximal and distal convoluted tubules, including the sodium hydrogen exchanger 3 (NHE3) and sodium chloride cotransporter (NCC). In conjunction with salt and water retention, T cell activation causes an increase in renal ROS production, and renal injury and fibrosis, all of which lead to renal dysfunction. The culmination of vascular and renal dysfunction caused by T cell–derived cytokines exacerbates hypertension (Illustration credit: Ben Smith). [Poweropint File]