title: Tetrahydrobiopterin reverse left ventricular hypertrophy and diastolic dysfunction through the PI3K/p-Akt pathway in spontaneously hypertensive rats.
abstract: Hypertension induced hypertrophy and diastolic dysfunction and is associated with cardiac oxidation and reduced NO production. We hypothesized that tetrahydrobiopterin (BH4) can regulate the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway and reverse cardiac hypertrophy and diastolic dysfunction in spontaneously hypertensive rats. Ten-week-old male spontaneously hypertensive rats (SHR) and age-matched normotensive control Wistar-Kyoto (WKY) rats were divided into five groups, WKY, WKY + BH4, SHR, SHR + BH4 and SHR + VAL. In SHR, diastolic dysfunction was accompanied by concentric hypertrophy, cardiac oxidation, and reduced cardiac BH4 and NO production. Four-week BH4 and valsartan administration reversed hypertrophy and improved diastolic function. BH4 and valsartan blunted the expression of hypertrophy markers α-skeletal actin (α-SA) and β-myosin heavy chain (β-MHC). Only BH4 reduced hypertension and induced myocardial fibrosis and expression of transforming growth factor-β1 (TGF-β1). BH4 reduced cardiac oxidant stress and increased NO production. Exogenous BH4 increased phosphorylated Akt levels and increased Bcl-2 expression. In conclusion, less BH4 and reduced NO increases myocardial hypertrophy and cardiac oxidative stress, which exacerbates diastolic dysfunction. Exogenous BH4 ameliorates cardiac hypertrophy and diastolic dysfunction through the PI3K/p-Akt pathway. BH4 may be a potent therapy for hypertension with diastolic dysfunction.
authors.affiliation: Department of Cardiology, Lanzhou University Second Hospital, Gansu, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Chang
authors.affiliation: Department of Cardiology, Lanzhou University Second Hospital, Gansu, China.
authors.forename: Qiongying
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Lanzhou University Second Hospital, Gansu, China.
authors.forename: Han
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Cardiology, Lanzhou University Second Hospital, Gansu, China.
authors.forename: Mina
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Lanzhou University Second Hospital, Gansu, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Cardiology, Lanzhou University Second Hospital, Gansu, China.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of General Medicine, Lanzhou University Second Hospital, Gansu, China.
authors.forename: Zhengyi
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Lanzhou University Second Hospital, Gansu, China.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Lanzhou University Second Hospital, Gansu, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, Lanzhou University Second Hospital, Gansu, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, Lanzhou University Second Hospital, Gansu, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Bai
authors.affiliation: Department of Cardiology, Lanzhou University Second Hospital, Gansu, China. Electronic address: yujing2304@126.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Yu
mesh_terms: D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D001794:Blood Pressure; D001835:Body Weight; D003971:Diastole / Q000187:drug effects*; D006973:Hypertension / Q000150:complications; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D009929:Organ Size; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000068756:Valsartan
chemical_list: D013777:Tetrazoles; D001708:Biopterins; D000068756:Valsartan; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C003402:sapropterin; D014633:Valine
keywords: Cardiac oxidation; Diastolic dysfunction; Hypertrophy; Phosphorylated Akt; Tetrahydrobiopterin