Posts Tagged: renin-angiotensin system

Diabetic Cardiomyopathy: An Update of Mechanisms Contributing to This Clinical Entity

Diabetic Cardiomyopathy: An Update of Mechanisms Contributing to This Clinical Entity

Guanghong Jia, Michael A. Hill, James R. Sowers

The molecular proteins and signaling pathways in hyperglycemia- and insulin resistance-diabetic cardiomyopathy. Increased protein kinase C (PKC), mitogen-activated protein kinase (MAPK), nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), sodium–glucose cotransporter-2 (SGLT2), O-linked N-acetylglucosamine (O-GlcNAc), and cyclic adenosine 5’-monophosphate-responsive element modulator (CREM) signaling, dysregulation of microRNA (miRNA) and exosomes, and reduction of AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor (PPAR)-γ, and nuclear factor erythroid 2–related factor 2 (Nrf2) induce cardiac insulin resistance, subcellular component abnormalities, metabolic disorders, and structural changes, resulting in diabetic cardiomyopathy. [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]