title: cAMP-PKA-CaMKII signaling pathway is involved in aggravated cardiotoxicity during Fuzi and Beimu Combination Treatment of Experimental Pulmonary Hypertension.
abstract: Aconiti Lateralis Radix Praeparata (Fuzi) and Fritillariae Thunbergii bulbus (Beimu) have been widely used clinically to treat cardiopulmonary related diseases in China. However, according to the classic rules of traditional Chinese medicine, Fuzi and Beimu should be prohibited to use as a combination for their incompatibility. Therefore, it is critical to elucidate the paradox on the use of Fuzi and Beimu combination therapy. Monocrotaline-induced pulmonary hypertension rats were treated with either Fuzi, Beimu, or their combination at different stages of PH. We demonstrated that at the early stage of PH, Fuzi and Beimu combination significantly improved lung function and reduced pulmonary histopathology. However, as the disease progressed, when Fuzi and Beimu combination were used at the late stage of PH, right ventricular chamber dilation was histologically apparent and myocardial apoptosis was significantly increased compared with each drug alone. Western-blotting results indicated that the main chemical ingredient of Beimu could down-regulate the protein phosphorylation levels of Akt and PDE4D, whereas the combination of Fuzi and Beimu could up-regulate PKA and CaMKII signaling pathways. Therefore, we concluded that Fuzi and Beimu combination potentially aggravated the heart injury due to the inhibition of PDK1/Akt/PDE4D axis and subsequent synergistic activation of βAR-Gs-PKA/CaMKII signaling pathway.
authors.affiliation: Chinese Materia Medica College, Tianjin University of Traditional Chinese Medicine, Tianjin, China.|Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
authors.forename: Pengwei
authors.initials: P
authors.lastname: Zhuang
authors.affiliation: Chinese Materia Medica College, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Chinese Materia Medica College, Tianjin University of Traditional Chinese Medicine, Tianjin, China.|School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Chinese Materia Medica College, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Chinese Materia Medica College, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
authors.forename: Liman
authors.initials: L
authors.lastname: Xu
authors.affiliation: Chinese Materia Medica College, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
authors.forename: Fengjiao
authors.initials: F
authors.lastname: Sun
authors.affiliation: Chinese Materia Medica College, Tianjin University of Traditional Chinese Medicine, Tianjin, China.|Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Jinao
authors.initials: J
authors.lastname: Duan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D004224:Diterpenes; D004338:Drug Combinations; D004365:Drugs, Chinese Herbal; D004452:Echocardiography; D006439:Hemodynamics; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D000070396:Liliales / Q000737:chemistry; D008297:Male; D009206:Myocardium / Q000473:pathology; D010936:Plant Extracts / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction
chemical_list: D004224:Diterpenes; D004338:Drug Combinations; D004365:Drugs, Chinese Herbal; D010936:Plant Extracts; C575009:fuzi drug herbal; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2