Protective Arm Of Renin Angiotensin System Research Articles

Mechanisms of neuro- and cardioprotection of MAS agonists in the TAC model.

Alzheimer's (AD) is a debilitating disease characterized by a loss of memory and executive function. A growing number of studies have shown a direct correlation between hypertension and increased risk of AD-like symptoms, including cognitive deficits, increased Aβ production and neuronal death. Furthermore, Renin-Angiotensin System (RAS) targeted anti-hypertensives reduce risk. This has prompted studies demonstrating that the protective arm of RAS, via activation of the MAS receptor, is reduced in AD patients, suggesting MAS agonists may protect against ROS production and exotoxicity while also increasing cognition and being cardioprotective. We hypothesize that MAS agonists can ameliorate AD-like pathology in mice using a model of heart failure - transverse aortic constriction (TAC). One week after TAC surgery, C57Bl/6J male mice (8-10wk) started treatment with saline or one of four Mas agonists. Four weeks after surgery, cardiac function was assessed by echocardiography followed by cognitive assessment (10 weeks) using novel object recognition. At 90days, brain, heart and blood were collected and analyzed for phenotypic and functional changes. TAC surgery induced marked morphological changes in cardiac tissue (cardiomyocyte area, fibrosis and apoptosis). The subsequent dysfunction manifested as decreases in standard cardiac measures of left ventricular function and by extension - cognition, which were rescued by MAS agonists. This treatment effect is partly due to a protection of the mitochondrial oxidative phosphorylation pathway rather than biogenesis. Specifically, marked ROS-induced mitochondrial dysfunction occurring within neurons and microglia were reduced with MAS agonist treatment. Further Seahorse analysis revealed a resistance to TAC-induced reductions in mitochondrial complex activity. This trend extended to the heart, improving outcomes for endothelial cells and cardiomyocytes. The Mas agonist RASRx1902 significantly decreased several measures of AD-like pathology in the TAC model with particular focus on cardioprotection and mitochondrial function, indicating that it may be beneficial in those with hypertension as a risk factor for AD development. Future work will focus on further characterizing RASRx1902 effects in affected cellular pathway changes, efficacy in a pilot study examining cerebral blood flow, blood brain barrier integrity, and effects on neuronal function.

Abstract 371: Cardiac Fibrosis is Associated With Increased Gut Barrier Leakage and Circulating Peptidoglycan in Type 2 Diabetic Mice With Ace2 Deficiency

Purpose: Cardiac fibrosis is linked with hyperglycemia and increases the risk of cardiovascular complications and heart failure. Despite several advancements, the molecular mechanisms responsible for cardiac fibrosis in diabetes remain unclear. The renin-angiotensin system (RAS) is activated and plays an essential role in diabetes-induced cardiac dysfunctions through activation of Ang II. However, angiotensin converting enzyme 2 (ACE2), the protective arm of RAS, opposes the classical RAS functions mediated by ACE. Previously, we have reported that ACE2 deficient exacerbates hyperglycemia-induced gut dysbiosis, increased gut barrier permeability, and facilities translocation of gut microbial peptides (GMPs) into system circulation in type 1 diabetic mice. Here, we sought to determine whether dysbiosis induced by type 2 diabetes and ACE2 deficiency contributes to cardiac fibrosis. Methods: Toll-like receptor- (TLR-2) associated inflammatory signaling and cardiac fibrosis were studied in WT, db/db, and ACE2 -/y -db/db mice with 4-months of diabetes. The levels of peptidoglycan (PGN), a TLR-2 ligand, were measured by ELISA assay. The markers of gut barriers and inflammatory cytokines were assessed by immunohistochemistry and qRT-PCR. To measure cardiac fibrosis, Masson’s trichrome staining was used to stain collagen fibers. Results: ACE2 -/y -db/db mice exhibited increased myocardial fibrosis as compared with db/db and WT mice. In the myocardium, TLR-2 expression (4 folds, p<0.005) and pro-inflammatory cytokines IL-1β (p<0.001), IL-6 (p<0.0001), and TNF-α (p<0.01 were significantly up-regulated in ACE2 -/y -db/db mice compared with db/db and WT mice. Increased gut barrier permeability as detected by a reduction in expression of tight junction molecules (ZO-1, p120-catenin, and VE-cadherin) and a 2- fold increase in circulating PGN was observed in ACE2 -/y -db/db mice when compared to db/db. Conclusions: These data suggest that PGN and other circulating gut microbial particles may have a deleterious impact on cardiac health by promoting inflammation-mediated fibrosis. In addition to controlling hyperglycemia, strategies aimed at restoring gut barrier integrity may prevent diabetic cardiovascular complications.

Targeting the Protective Arm of the Renin-Angiotensin System to Reduce Systemic Lupus Erythematosus Related Pathologies in MRL-lpr Mice

Patients with Systemic Lupus Erythematosus (SLE) suffer from a chronic inflammatory autoimmune disease that results from the body's immune system targeting healthy tissues which causes damage to various organ systems. Patients with lupus are still in need of effective therapies to treat this complex, multi-system disease. Because polymorphisms in ACE are associated with the activity of SLE and lupus nephritis and based on well-documented renal-protective effects of Renin Angiotensin System (RAS)-modifying therapies, ACE-I are now widely used in patients with SLE with significant efficacy. Our research explores alternate ways of modifying the RAS as a potential for systemic therapeutic benefit in the MRL-lpr mouse model of SLE. These therapeutics include; angiotensin (1-7) [A(1-7)], Nor-Leu-3 Angiotensin (1-7) (NorLeu), Losartan (ARB), and Lisinopril (ACE-I). Daily systemic treatment with all of these RAS-modifying therapies significantly reduced the onset and intensity in rash formation and swelling of the paw. Further, histology showed a corresponding decrease in hyperkeratosis and acanthosis in skin sections. Important immunological parameters such as decreased circulating anti-dsDNA antibodies, lymph node size, and T cell activation were observed. As expected, the development of glomerular pathologies was also attenuated by RAS-modifying therapy. Improved number and health of mesenchymal stem cells (MSCs), as well as reduction in oxidative stress and inflammation may be contributing to the reduction in SLE pathologies. Several studies have already characterized the protective role of ACE-I and ARBs in mouse models of SLE, here we focus on the protective arm of RAS. A(1-7) in particular demonstrates several protective effects that go beyond those seen with ACE-Is and ARBs; an important finding considering that ACE-Is and ARBs are teratogenic and can cause hypotension in this population. These results offer a foundation for further pharmaceutical development of RAS-modifying therapies, that target the protective arm, as novel SLE therapeutics that do not rely on suppressing the immune system.

Activation of the Protective Arm of the Renin Angiotensin System in Demyelinating Disease.

The renin angiotensin system (RAS), which is classically known for blood pressure regulation, has functions beyond this. There are two axes of RAS that work to counterbalance each other and are active throughout the body, including the CNS. The pathological axis, consisting of angiotensin II (A1-8), angiotensin converting enzyme (ACE) and the angiotensin II type 1 receptor (AT1R), is upregulated in many CNS diseases, including multiple sclerosis (MS). MS is an autoimmune and neurodegenerative disease of the CNS characterized by inflammation, demyelination and axonal degeneration. Published research has described increased expression of AT1R and ACE in tissues from MS patients and in animal models of MS such as experimental autoimmune encephalomyelitis (EAE). In contrast to the pathological axis, little is known about the protective axes of RAS in MS and EAE. In other neurological conditions the protective axis, which includes A1-7, ACE2, angiotensin II type 2 receptor and Mas receptor, has been shown to have anti-inflammatory, regenerative and neuroprotective effects. Here we show, for the first time, changes in the protective arm of RAS in both EAE and MS CNS tissue. We observed a significant increase in expression of the protective arm during stages of disease stabilization in EAE, and in MS tissue showing evidence of remyelination. These data provide evidence that the protective arm of RAS, through both ligand and receptor expression, is associated with reductions in the pathological processes that occur in the earlier stages of MS and EAE, possibly slowing the neurodegenerative process and enhancing neural repair. Graphical Abstract.

MAS AGONISTS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASE

Alzheimer's disease (AD) is associated with loss of memory and executive function. Several studies have shown a direct correlation between hypertension and an increased incidence of AD like symptoms, including cognitive deficits and increased Aβ deposition. Most interestingly, individuals who are on anti-hypertensive medications (angiotensin receptor blockers and angiotensin converting enzyme inhibitors) targeting the Renin-Angiotensin System (RAS), have a reduced risk of developing AD. Recently, the protective arm of RAS, angiotensin (1-7)[A(1-7)]/Mas receptor/angiotensin converting enzyme 2, is reduced in AD patients. Mas activation increases cognition and is cardioprotective. Thus, we hypothesized that Mas agonists could help ameliorate AD-like pathology. Mice underwent transaortic constriction (TAC), a mouse model of heart failure and hypertension. One week after induction of TAC, mice started treatment with saline or one of three Mas agonists. Seven weeks after surgery, the cardiac function was assessed by echocardiography followed by assessment of their cognitive abilities (8 weeks) using novel object recognition. Upon necropsy, brain, heart, bone marrow and blood were collected. TAC surgery decreased cognition and increased mitochondrial oxidative stress (OS) in neurons and microglia. Treatment with Mas agonists increased cognition and reduced brain OS. Further, treatment with Mas agonists reduced inflammatory cytokines in the hippocampus. These data support the development of Mas agonist for the treatment of neurodegenerative diseases.

The angiotensin type 2 receptor in the human adrenocortical zona glomerulosa and in aldosterone-producing adenoma: low expression and no functional role.

The angiotensin II (Ang II) type 2 receptor (AT2R) and the angiotensin-(1-7) (Ang-(1-7)) receptor (MasR) play a cardiovascular protective role by counter-regulating Ang II type 1 receptor (AT1R)-mediated effects, but whether this involves blunting of adrenocortical hormone secretion is unknown. We investigated the presence of AT1R, AT2R, and MasR in aldosterone-producing adenoma (APA), a condition featuring hyperaldosteronism, and in APA-adjacent tissue. The effect of Compound 21 (C21), an AT2R agonist, on CYP11B1 (cortisol synthase) and CYP11B2 (aldosterone synthase) gene expression in NCI-H295R and HAC15 cell lines, and in APA and APA-adjacent tissue, was also assessed using the AT1R antagonist irbesartan to ascertain the specificity of C21 effect. We found that the AT1R, AT2R, and MasR were expressed in APA and APA-adjacent tissue, albeit heterogeneously. The gene expression of AT1R and AT2R was lower, and that of the MasR higher in APAs than in APA-adjacent tissue. In steroid-producing NCI-H295R and HAC15 cell lines, and in APA and APA-adjacent tissue, C21 was ineffective at nanomolar concentrations, but increased CYP11B1 and CYP11B2 gene expression at micromolar concentrations through AT1R, as this effect was blunted by irbesartan. The scant expression of the AT2R, along with the lack of any effect of C21 at low concentrations on CYP11B2, do not support the contention that the protective arm of renin-angiotensin system (RAS) blunts aldosterone synthase in the normal adrenal cortex and primary aldosteronism.

Emerging Pharmacological Treatments to Prevent Abdominal Aortic Aneurysm Growth and Rupture

Abdominal aortic aneurysm (AAA) is a local expansion of the abdominal aorta wall caused by a complex multifactorial maladaptive vascular remodeling. Despite recent advances in the management of cardiovascular diseases, there currently is no established drug therapy for AAA. Since the probability of death from a ruptured AAA still remains high, preventive elective repair of AAAs larger than 5.5 cm in luminal diameter is considered the best treatment option. However, perioperative complications are problematic as elective AAA repair comes with numerous intrinsic risks. Impelled by the need of improving AAA therapy, significant efforts have been made to identify pharmacological tools that would slow down AAA enlargement and lower the risk of rupture, thereby reducing the necessity of surgical intervention. In this review, we discuss recent findings addressing molecular targets that could potentially treat AAA, particularly addressing: statins, classical renin angiotensin system (RAS) blockers, the protective arm of RAS, renin inhibitors, tetracyclines, interleukin-1β inhibition, anti-angiogenic agents and urocortins.