This study aimed to investigate the anti-fibrotic effects of ghrelin in isoproterenol (ISO)-induced myocardial fibrosis and the underlying mechanism. Sprague-Dawley rats were randomized to control, ISO, and ISO + ghrelin groups. ISO (2 mg/kg per day, subcutaneous) or vehicle was administered once daily for 7 days, then ghrelin (100 microg/kg per day, subcutaneous) was administered once daily for the next 3 weeks. Ghrelin treatment greatly improved the cardiac function of ISO-treated rats. Ghrelin also decreased plasma brain natriuretic peptide level and ratios of heart weight to body weight and left ventricular weight to body weight. Ghrelin significantly reduced myocardial collagen area and hydroxyproline content, accompanied by decreased mRNA levels of collagen type I and III. Furthermore, ghrelin increased plasma level of growth differentiation factor 15 (GDF15) and GDF15 mRNA and protein levels in heart tissues, which were significantly decreased with ISO alone. The phosphorylation of Akt at Ser473 and GSK-3beta at Ser9 was decreased with ISO, and ghrelin significantly reversed the downregulation of p-Akt and p-GSK-3beta. Mediated by GDF15, ghrelin could attenuate ISO-induced myocardial fibrosis via Akt-GSK-3beta signaling.
- MeSH
- Adrenergic beta-Agonists pharmacology MeSH
- Fibrosis chemically induced drug therapy pathology MeSH
- Ghrelin administration & dosage MeSH
- Isoproterenol pharmacology MeSH
- Cardiomyopathies chemically induced drug therapy metabolism pathology MeSH
- Rats MeSH
- Disease Models, Animal MeSH
- Myocardium metabolism pathology MeSH
- Rats, Sprague-Dawley MeSH
- Proto-Oncogene Proteins c-akt metabolism MeSH
- Growth Differentiation Factor 15 metabolism MeSH
- Heart drug effects physiopathology MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Proximal resistance vessels, such as the mesenteric arteries, contribute substantially to the peripheral resistance. The reactivity of resistance vessels to vasoactive substance like natriuretic peptides plays an important role in the regulation of blood pressure. In current study, we investigated the reactivity of mesenteric arteries to atrial natriuretic peptide (ANP), a well known vasodilating factor, in spontaneously hypertensive rats (SHR), as well as the effects of exercise training on it. As a result, ANP-induced vasorelaxation was attenuated in SHR with significantly increased phosphodiesterase type 5 (PDE5), and decreased cGMP/ANP ratio, compared with WKY rats as control. Intriguingly, the decreased reactivity to ANP in SHR was markedly reversed by exercise training. In addition, ANP resistance of in vitro mesenteric arteries was diminished by sildenafil a potent selective inhibitor of PDE5. In conclusion, ANP resistance occurs in resistance vessels of SHR, suggesting predisposition to hypertension, which can be reversed by exercise.
- MeSH
- Mesenteric Arteries drug effects physiology MeSH
- Atrial Natriuretic Factor pharmacology therapeutic use MeSH
- Hypertension drug therapy physiopathology therapy MeSH
- Physical Conditioning, Animal methods physiology MeSH
- Blood Pressure drug effects physiology MeSH
- Rats MeSH
- Drug Resistance MeSH
- Rats, Inbred SHR MeSH
- Rats, Inbred WKY MeSH
- Vasodilation drug effects physiology MeSH
- Dose-Response Relationship, Drug MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
