alamandine and Cardiomegaly

L’alamandine, une nouvelle molécule d’intérêt thérapeutique contre l’hypertrophie cardiaque.. Pour la cinquième année, dans le cadre du module d’enseignement « Physiopathologie de la signalisation » proposé par l’université Paris-sud, les étudiants du Master « Biologie Santé » de l’université Paris-Saclay se sont confrontés à l’écriture scientifique. Ils ont sélectionné une quinzaine d’articles scientifiques récents dans le domaine de la signalisation cellulaire présentant des résultats originaux, via des approches expérimentales variées, sur des thèmes allant des relations hôte-pathogène aux innovations thérapeutiques, en passant par la signalisation hépatique et le métabolisme. Après un travail préparatoire réalisé avec l’équipe pédagogique, les étudiants, organisés en binômes, ont ensuite rédigé, guidés par des chercheurs, une Nouvelle soulignant les résultats majeurs et l’originalité de l’article étudié. Ils ont beaucoup apprécié cette initiation à l’écriture d’articles scientifiques et, comme vous pourrez le lire, se sont investis dans ce travail avec enthousiasme ! Trois de ces Nouvelles sont publiées dans ce numéro, les autres le seront dans des prochains numéros.

Topics: Cardiomegaly; Humans; Myocytes, Cardiac; Oligopeptides

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

Topics: AMP-Activated Protein Kinases; Angiotensin II; Animals; Cardiomegaly; Cells, Cultured; Enzyme Activation; Male; Mice, Inbred C57BL; Mice, Knockout; Myocytes, Cardiac; Nerve Tissue Proteins; Nitric Oxide; Oligopeptides; Phosphorylation; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats, Wistar; Receptors, G-Protein-Coupled; Signal Transduction

Oral administration of the peptide alamandine has antihypertensive and anti-fibrotic effects in rats. This work aimed to determine whether subcutaneous alamandine injection would attenuate hypertension and cardiac hypertrophy, and improve the function of a major target of hypertension-related damage, the left ventricle (LV), in spontaneously hypertensive rats (SHRs). This was examined in vivo in SHRs and normotensive rats subjected to 6-week subcutaneous infusion of alamandine or saline control, and in vitro in H9C2-derived and primary neonatal rat cardiomyocytes treated with angiotensin (Ang) II to model cardiac hypertrophy. Tail artery blood pressure measurement and transthoracic echocardiography showed that hypertension and impaired LV function in SHRs were ameliorated upon alamandine infusion. Alamandine administration also decreased the mass gains of heart and lung in SHRs, suppressed cardiomyocyte cross-sectional area expansion, and inhibited the mRNA levels of atrial natriuretic peptide and brain natriuretic peptide. The expression of alamandine receptor Mas-related G protein-coupled receptor, member D was increased in SHR hearts and in cardiomyocytes treated with Ang II. Alamandine inhibited the increases of protein kinase A (PKA) levels in the heart in SHRs and in cardiomyocytes treated with Ang II. In conclusion, the present study showed that alamandine administration attenuates hypertension, alleviates cardiac hypertrophy, and improves LV function. PKA signaling may be involved in the mechanisms underlying these effects.

Topics: Angiotensins; Animals; Antihypertensive Agents; Cardiomegaly; Cell Line; Cyclic AMP-Dependent Protein Kinases; Echocardiography; Heart Ventricles; Hypertension; Infusions, Subcutaneous; Injections, Subcutaneous; Male; Myocytes, Cardiac; Nerve Tissue Proteins; Oligopeptides; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled