angiotensin-i and Myocarditis

In human pathology, SARS-CoV-2 utilizes multiple molecular pathways to determine structural and biochemical changes within the different organs and cell types. The clinical picture of patients with COVID-19 is characterized by a very large spectrum. The reason for this variability has not been clarified yet, causing the inability to make a prognosis on the evolution of the disease.. PubMed search was performed focusing on the role of ACE 2 receptors in allowing the viral entry into cells, the role of ACE 2 downregulation in triggering the tissue pathology or in accelerating previous disease states, the role of increased levels of Angiotensin II in determining endothelial dysfunction and the enhanced vascular permeability, the role of the dysregulation of the renin angiotensin system in COVID-19 and the role of cytokine storm.. The pathological changes induced by SARS-CoV-2 infection in the different organs, the correlations between the single cell types targeted by the virus in the different human organs and the clinical consequences, COVID-19 chronic pathologies in liver fibrosis, cardiac fibrosis and atrial arrhythmias, glomerulosclerosis and pulmonary fibrosis, due to the systemic fibroblast activation induced by angiotensin II are discussed.. The main pathways involved showed different pathological changes in multiple tissues and the different clinical presentations. Even if ACE2 is the main receptor of SARS-CoV-2 and the main entry point into cells for the virus, ACE2 expression does not always explain the observed marked inter-individual variability in clinical presentation and outcome, evidencing the complexity of this disorder. The proper interpretation of the growing data available might allow to better classifying COVID-19 in human pathology.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Atrial Fibrillation; Blood Coagulation; Capillary Permeability; Cardiomyopathies; COVID-19; Cytokine Release Syndrome; Cytokines; Endothelium, Vascular; Fibroblasts; Fibrosis; Humans; Liver Cirrhosis; Myocarditis; Receptors, Coronavirus; Renin-Angiotensin System; SARS-CoV-2; Systemic Inflammatory Response Syndrome; Thrombosis; Virus Internalization

Although renin-angiotensin system (RAS) imbalance is manifested in cardiomyopathies with different etiologies, the impact of RAS effectors on Chagas cardiomyopathy and skeletal myositis is poorly understood. Given that diminazene aceturate (DMZ) shares trypanocidal, angiotensin-converting enzyme 2 (ACE2) and angiotensin-(1-7) stimulatory effects, we investigated the impact of DMZ on cardiomyocytes infection in vitro, renin-angiotensin system, Chagas cardiomyopathy and skeletal myositis in vivo. Cardiomyocytes and T. cruzi were used to evaluate DMZ toxicity in vitro. The impact of 20-days DMZ treatment (1 mg/kg) was also investigated in uninfected and T. cruzi-infected mice as follows: control uninfected and untreated, uninfected treated with DMZ, infected untreated and infected treated with DMZ. DMZ had low toxicity on cardiomyocytes, induced dose-dependent antiparasitic activity on T. cruzi trypomastigotes, and reduced parasite load but not infection rates in cardiomyocytes. DMZ increased ACE2 activity and angiotensin-(1-7) plasma levels but exerted no interference on angiotensin-converting enzyme (ACE) activity, ACE, ACE2 and angiotensin II levels in uninfected and infected mice. DMZ treatment also reduced IFN-γ and IL-2 circulating levels but was ineffective in attenuating parasitemia, MCP-1, IL-10, anti-T. cruzi IgG, nitrite/nitrate and malondialdehyde production, myocarditis and skeletal myositis compared to infected untreated animals. As the antiparasitic effect of DMZ in vitro did not manifest in vivo, this drug exhibited limited relevance to the treatment of Chagas disease. Although DMZ is effective in upregulating angiotensin-(1-7) levels, this molecule does not act as a potent modulator of T. cruzi infection, which can establish heart and skeletal muscle parasitism, lipid oxidation and inflammatory damage, even in the presence of high concentrations of this RAS effector.

Topics: Angiotensin I; Animals; Cell Line; Chagas Cardiomyopathy; Chagas Disease; Diminazene; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred BALB C; Myocarditis; Myocytes, Cardiac; Myositis; Peptide Fragments; Rats; Renin-Angiotensin System; Trypanocidal Agents

Candesartan cilexetil, an angiotensin (Ang) II receptor 1 blocker was reported to suppress the myocardial damage in various cardiovascular complications but the mode by which it is effective in preventing the progression of dilated cardiomyopathy (DCM) is unknown. Emerging evidences suggest that, at least, part of the benefits observed with the use of AT1 receptor blockers could be attributed to the increased Ang (1-7) levels observed during administration of these agents. Identification of the novel components of the RAS, ACE2 and Ang (1-7) receptor mas, provided essential elements for considering the existence of a vasodilator arm of the RAS, represented by the ACE2-Ang (1-7)-mas axis. In this study, rat model of DCM was prepared by injection with porcine cardiac myosin. Twenty-eight days after immunization, candesartan cilexetil was administered intraperitoneally at 1 or 10mg/kg/day to rats for four weeks. Myocardial expression of Ang receptors and markers of calcium homeostasis, endoplasmic reticulum (ER) stress and apoptosis were measured by Western blotting and histopathological staining techniques. Candesartan improved the functional markers in a dose-dependent manner and also upregulated Ang (1-7), ACE2 and mas1 in the myocardium of DCM rats. Various ER stress and apoptosis markers were attenuated and the number apoptotic cells were significantly lower in the candesartan treated rats compared with those of the vehicle group. These findings suggest that candesartan treatment prevented the progression of DCM by activation of the counter regulatory arm of the RAS and possibly through modulation of ER stress and subsequently, cardiac apoptosis.

Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme 2; Animals; Apoptosis; Apoptosis Regulatory Proteins; Autoimmune Diseases; Benzimidazoles; Biphenyl Compounds; Blotting, Western; Cell Survival; Endoplasmic Reticulum Stress; Heart Diseases; Immunohistochemistry; In Situ Nick-End Labeling; Male; Myocarditis; Myosins; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats; Rats, Inbred Lew; Receptors, G-Protein-Coupled; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Signal Transduction; Tetrazoles

Angiotensin-converting enzyme 2 (ACE-2) is a membrane-associated carboxy-peptidase catalyzes the conversion of the vasoconstrictor angiotensin (ANG)-II to the vasodilatory peptide ANG 1-7. In view of the expanding axis of the renin angiotensin system, we have investigated the cardioprotective effects of olmesartan (10mg/kg/day) in experimental autoimmune myocarditis. Olmesartan treatment effectively suppressed the myocardial protein expressions of inflammatory markers in comparison to the vehicle-treated rats. However, the protein and mRNA levels of ACE-2 and ANG 1-7, and its receptor Mas were upregulated in olmesartan treated group compared to vehicle-treated rats. Olmesartan medoxomil treatment significantly decreased the expression levels of phospho-p38 mitogen-activated protein kinase (MAPK), phospho-JNK, phospho-ERK and phospho-(MAPK) activated protein kinase-2 than with those of vehicle-treated rats. Moreover, vehicle-treated rats were shown to be up-regulated protein expressions of NADPH oxidase subunits (p47phox, p67phox and Nox-4), myocardial apoptotic markers and endoplasmic reticulum stress markers in comparison to those of normal and all these effects are expectedly down-regulated by an olmesartan. In addition, attenuated protein levels of phosphatidylinositol-3-kinase (PI3K) and phospho-Akt in the vehicle-treated EAM rats were prevented by olmesartan treatment. Our results suggest that beneficial effects of olmesartan treatment was more effective therapy in combating the inflammation, oxidative stress, apoptosis and signaling pathways associated with heart failure at least in part via the modulation of ANG 1-7 mas receptor.

Topics: Angiotensin I; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme 2; Animals; Apoptosis; Autoimmune Diseases; Cardiotonic Agents; Endoplasmic Reticulum Stress; Heart Failure; Imidazoles; Inflammation; JNK Mitogen-Activated Protein Kinases; Membrane Glycoproteins; Myocarditis; NADPH Oxidase 4; NADPH Oxidases; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Peptide Fragments; Peptidyl-Dipeptidase A; Phosphatidylinositol 3-Kinases; Phosphoproteins; Proto-Oncogene Proteins c-akt; Rats; Rats, Inbred Lew; Receptor, Angiotensin, Type 1; Receptors, Interleukin-1; RNA, Messenger; Tetrazoles

Angiotensin-converting enzyme-2 (ACE-2) is a homolog of ACE that preferentially forms angiotensin-(ANG)-1-7 from angiotensin II (ANG II). We investigated the cardioprotective effects of telmisartan, a well-known angiotensin receptor blockers (ARBs) against experimental autoimmune myocarditis (EAM). EAM was induced in Lewis rats by immunization with porcine cardiac myosin. The rats were divided into two groups and treated with telmisartan (10 mg/kg/day) or vehicle for 21 days. Myocardial functional parameters were significantly improved by treatment with telmisartan compared with vehicle-treated rats. Telmisartan lowered myocardial protein expressions of NADPH oxidase subunits 3-nitrotyrosine, p47phox, p67 phox, Nox-4 and superoxide production significantly than vehicle-treated rats. In contrast myocardial protein levels of ACE-2, ANG 1-7 mas receptor were upregulated in the telmisartan treated group compared with those of vehicle-treated rats. The myocardial protein expression levels of tumor necrosis factor receptor (TNFR)-associated factor (TRAF)-2, C/EBP homologous protein (CHOP) and glucose-regulated protein (GRP) 78 were decreased in the telmisartan treated rats compared with those of vehicle-treated rats. In addition, telmisartan treatment significantly decreased the protein expression levels of phospho-p38 mitogen-activated protein kinase (MAPK), phospho-JNK, phospho-ERK and phospho (MAPK) activated protein kinase-2 than with those of vehicle-treated rats. Moreover, telmisartan significantly decreased the production of proinflammatory cytokines, myocardial apoptotic markers and caspase-3 positive cells compared with those of vehicle-treated rats. Therefore, we suggest that telmisartan was beneficial protection against heart failure in rats, at least in part by suppressing inflammation, oxidative stress, ER stress as well as signaling pathways through the modulation of ACE2/ANG1-7/Mas receptor axis.

Topics: Angiotensin I; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme 2; Animals; Apoptosis; Benzimidazoles; Benzoates; Biomarkers; Cytokines; Disease Models, Animal; Endoplasmic Reticulum; Heart Failure; Male; Mitogen-Activated Protein Kinases; Myocarditis; NADPH Oxidases; Oxidative Stress; Peptide Fragments; Peptidyl-Dipeptidase A; Protective Agents; Protein Subunits; Rats; Signal Transduction; Superoxides; Telmisartan

The progression of aortic stenosis (AS) has been shown to be faster in patients with the metabolic syndrome. We sought to determine the relationships between blood pressure, inflammation, oxidative stress and valvular inflammation in a population of normotensive and prehypertensive patients with AS.. In this study, 36 male patients (age: 61.5±2 years) with AS undergoing an aortic valve replacement were investigated. Plasma levels of adiponectin, oxidized-LDL (ox-LDL), angiotensinogen (AGN) and angiotensin I-II (Ang I-II) were measured. On explanted aortic valves, immunohistochemistry studies and quantitative PCR (q-PCR) analyses were performed to document the expression of inflammatory cytokines.. Systolic blood pressure (SBP) was positively correlated with plasma level of ox-LDL (r=0.4; p=0.02), AGN (r=0.41; p=0.01), and white blood cells count (r=0.33; p=0.04), whereas it was inversely related to plasma level of adiponectin (r=-.35; p=0.04). After adjustment for covariates, plasma level of ox-LDL (p=0.01) remained significantly associated with SBP (p=0.01). Within the aortic valve, expression of TNF-α was significantly associated with plasma levels of ox-LDL (r=0.58; p=0.03), Ang II (r=0.69; p=0.013), and waist circumference (r=0.60; p=0.02), whereas valvular expression of IL-6 was associated with plasma level of Ang II (r=0.51; p=0.03). In explanted AS valves, ox-LDL was documented near calcified areas and colocalized with Ang II, IL-6, and TNF-α.. Conditions associated with a higher oxidative stress and activation of the renin angiotensin system, such as encountered in viscerally obese and prehypertensive patients, contribute to higher valvular inflammation in AS.

Topics: Adiponectin; Angiotensin I; Angiotensin II; Angiotensinogen; Aortic Valve Stenosis; Biomarkers; Blood Pressure; Humans; Interleukin-6; Linear Models; Lipoproteins, LDL; Male; Middle Aged; Multivariate Analysis; Myocarditis; Oxidative Stress; Prehypertension; Renin-Angiotensin System; Tumor Necrosis Factor-alpha; Waist Circumference

Recovery from viral myocarditis is usually excellent and complete although it occasionally results in sudden death during its acute stage. While neurohormonal mechanisms play an important role in the adaptation to heart diseases, little is known about the alteration of the neurohormonal system in viral myocarditis. Therefore, we examined the myocardial beta-adrenergic receptor and cardiac angiotensin I and II concentrations in a murine model of viral myocarditis induced by an encephalomyocarditis virus. The down-regulation of the beta 1-adrenergic receptor subtype was observed on day 10. The heart weight, heart weight/body weight ratio and myocardial necrosis were significantly increased at this stage. On day 30, the beta 2-adrenergic receptor subtype was up-regulated without up-regulation of the total beta-adrenergic receptor. Both angiotensin I and II concentrations were significantly increased with myocardial hypertrophy in the left ventricle on day 30. The up-regulation of the total beta-adrenergic receptor and beta 2-subtype was observed on day 120, but neither the angiotensin I nor II concentration was increased. Therefore, the up-regulation of the beta 2-adrenergic receptor density and the temporal increase of the angiotensin I and II concentrations in the murine ventricle during viral myocarditis may play an important role in the pathophysiology of post-viral myocarditis.

Topics: Angiotensin I; Angiotensin II; Animals; Cardiovirus Infections; Down-Regulation; Encephalomyocarditis virus; Female; Iodocyanopindolol; Mice; Mice, Inbred C3H; Myocarditis; Myocardium; Pindolol; Radioligand Assay; Receptors, Adrenergic, beta; Up-Regulation