alamandine and Fibrosis

Angiotensin (Ang) II, the main active member of the renin angiotensin system (RAS), is essential for the maintenance of cardiovascular homeostasis. However, hyperactivation of the RAS causes fibrotic diseases. Ang II has pro-inflammatory actions, and moreover activates interstitial fibroblasts and/or dysregulates extracellular matrix degradation. The discovery of new RAS pathways has revealed the complexity of this system. Among the RAS peptides, alamandine (ALA, Ala

Topics: Angiotensin II; Animals; Anti-Inflammatory Agents; Antioxidants; Collagen; COVID-19 Drug Treatment; Fibrosis; Humans; Mice; Oligopeptides; Peptidyl-Dipeptidase A; Rats; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Vasodilator Agents

Alamandine (Ala) is the newest identified peptide of the renin-angiotensin system and has protective effect on myocyte hypertrophy. However, it is still unclear whether Ala can alleviate heart failure (HF). The aim of this study was to explore the effects of Ala on HF and the related cardiac fibrosis, and to probe the mechanism. HF model was induced by myocardial infarction (MI) in mice. Four weeks after MI, Ala was administrated by intraperitoneal injection for two weeks. Ala injection significantly improved cardiac dysfunction of MI mice in vivo. The cardiac fibrosis and the related biomarkers were attenuated after Ala administration in HF mice in vivo. The increases of collagen I, alpha-smooth muscle actin and transforming growth factor-beta induced by oxygen-glucose deprivation (OGD) in neonatal rat cardiac fibroblasts (NRCFs) were inhibited by Ala treatment in vitro. The biomarkers of apoptosis were elevated in NRCFs induced by OGD, which were attenuated after treating with Ala in vitro. The enhancement of oxidative stress in the heart of MI mice or in the NRCFs treated with OGD was suppressed by treating with Ala in vivo and in vitro. These effects of Ala were reversed by tBHP, an exogenous inducer of oxidative stress in vitro. These results demonstrated that Ala could alleviate cardiac dysfunction and attenuate cardiac fibrosis via inhibition of oxidative stress.

Topics: Actins; Animals; Biomarkers; Collagen Type I; Fibrosis; Glucose; Heart Failure; Mice; Myocardial Infarction; Myocardium; Oligopeptides; Oxygen; Rats; Transforming Growth Factors

Topics: Angiotensin II; Animals; Antihypertensive Agents; Aorta, Thoracic; Arterial Pressure; Cells, Cultured; Disease Models, Animal; Fibrosis; Hypertension; Male; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Nerve Tissue Proteins; Oligopeptides; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Signal Transduction; Vascular Remodeling

Cardiac fibrosis secondary to long‑term hypertension is known to promote cardiac dysfunction; however, few therapeutic agents are available for the treatment of this condition in clinical practice. The heptapeptide alamandine (Ala) has recently been identified as a component of the renin‑angiotensin system (RAS), which exerts a protective effect against cardiac hypertrophy; however, it is unknown whether Ala may also be useful for the treatment of cardiac fibrosis. In the present study, the potential therapeutic effects of Ala on long‑term hypertension‑induced cardiac fibrosis were investigated in an aged, spontaneous hypertensive rat model. Weekly blood pressure (BP) measurements revealed that daily Ala treatment significantly decreased the systolic, diastolic and mean arterial BP compared with the control. Of note, the observed reduction in BP in Ala‑treated animals markedly differed to that observed in rats treated with hydralazine (Hyd). Echocardiography further demonstrated that Ala treatment decreased the ratio of left ventricle mass to body weight, and alleviated structural and functional parameters associated with cardiac fibrosis, including left ventricular volume, ejection fraction and fractional shortening compared with the control and Hyd‑treated groups. Furthermore, Ala deceased the density of cardiac fibrosis, as assessed by Masson and Sirius red staining; reduced expression of fibrotic proteins, including connective tissue growth factor, collagen I (COL1A1) and matrix metalloproteinase 9, was also observed. In addition, Ala treatment further decreased the expression of angiotensin II‑induced fibrotic markers at the mRNA and protein levels in cultured cardiac fibroblasts; Ala‑mediated inhibition of COL1A1 expression and Akt phosphorylation was inhibited via the Mas‑related G protein receptor antagonist, PD123319. Collectively, the findings of the present study suggest that Ala is an effective anti‑hypertensive peptide that can attenuate cardiac dysfunction and fibrosis induced by chronic hypertension, independent of BP.

Topics: Angiotensin II; Animals; Antihypertensive Agents; Blood Pressure; Cardiomegaly; Collagen Type I; Collagen Type I, alpha 1 Chain; Fibrosis; Heart Ventricles; Hypertension; Imidazoles; Male; Matrix Metalloproteinase 9; Oligopeptides; Proto-Oncogene Proteins c-akt; Pyridines; Rats; Rats, Inbred SHR; Renin-Angiotensin System