β-Hydroxybutyrate inhibits cardiac microvascular collagen 4 accumulation by attenuating oxidative stress in streptozotocin-induced diabetic rats and high glucose treated cells

• Published in: European journal of pharmacology 2021-05, Vol.899, p.174012, Article 174012
• Main Authors: Qi, Huanli, Gu, Lihui, Xu, Dongmei, Liu, Kun, Zhou, Mingjie, Wang, Yu, Wang, Xiujuan, Li, Yanning, Qi, Jinsheng
• Format: Article
• Language: English
• Subjects: 3-Hydroxybutyric Acid - pharmacology; Animals; Antioxidants - pharmacology; Cells, Cultured; Collagen 4; Collagen Type IV - genetics; Collagen Type IV - metabolism; Coronary Vessels - drug effects; Coronary Vessels - metabolism; Coronary Vessels - pathology; Diabetes Mellitus, Experimental - chemically induced; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Diabetic cardiac microvascular fibrosis; Diabetic Cardiomyopathies - etiology; Diabetic Cardiomyopathies - metabolism; Diabetic Cardiomyopathies - pathology; Diabetic Cardiomyopathies - prevention & control; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelial Cells - pathology; Fibrosis; Glucose - toxicity; Humans; Inducible nitric oxide synthase; Male; Microvessels - drug effects; Microvessels - metabolism; Microvessels - pathology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Nitric Oxide Synthase Type II - metabolism; Oxidative Stress - drug effects; Peroxynitrite; Peroxynitrous Acid - metabolism; Rats; Rats, Sprague-Dawley; Streptozocin; Superoxide dismutase; Superoxide Dismutase-1 - metabolism; β-Hydroxybutyrate
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2021.174012

Accumulation of collagen 4 (COL4) and thickened basement membrane are features of diabetic cardiac microvascular fibrosis that may be induced by oxidative stress. The ketone body β-hydroxybutyrate exhibits various cardiovascular protective effects, however its mechanism remains to be clarified. In the current study, the effects of β-hydroxybutyrate on cardiac microvascular fibrosis and COL4 accumulation were evaluated in streptozotocin-induced diabetic rats and in high glucose (HG) treated human cardiac microvascular endothelial cells (HCMECs). Generations of inducible nitric oxide synthase (iNOS) and copper-zinc superoxide dismutase (Cu/Zn-SOD), and the amount of nitrotyrosine (NT) were measured in vivo and in vitro. Ten weeks of β-hydroxybutyrate treatment (160, 200 and 240 mg/kg/d) attenuated cardiac microvascular fibrosis and inhibited cardiac COL4 generation and microvascular distribution in diabetic rats. Furthermore, β-hydroxybutyrate promoted cardiac Cu/Zn-SOD generation and reduced NT content, without reducing iNOS generation in diabetic rats. In HCMECs, stimulation with HG induced excess generation of COL4 via peroxynitrite. β-Hydroxybutyrate treatment (2, 4, 6 mM) attenuated HG-stimulated COL4 accumulation in a concentration-dependent manner. Similarly, 4 mM β-hydroxybutyrate promoted Cu/Zn-SOD generation and reduced NT content, without affecting excess iNOS generation in HG-stimulated HCMECs. In conclusion, this study showed that β-hydroxybutyrate promoted Cu/Zn-SOD generation, reduced peroxynitrite and inhibited cardiac microvascular COL4 accumulation in diabetes.