title: Disruption of histamine H2 receptor slows heart failure progression through reducing myocardial apoptosis and fibrosis.
abstract: Histamine H2 receptor (H2R) blockade has been reported to be beneficial for patients with chronic heart failure (CHF), but the mechanisms involved are not entirely clear. In the present study, we assessed the influences of H2R disruption on left ventricular (LV) dysfunction and the mechanisms involved in mitochondrial dysfunction and calcineurin-mediated myocardial fibrosis. H2R-knockout mice and their wild-type littermates were subjected to transverse aortic constriction (TAC) or sham surgery. The influences of H2R activation or inactivation on mitochondrial function, apoptosis and fibrosis were evaluated in cultured neonatal rat cardiomyocytes and fibroblasts as well as in murine hearts. After 4 weeks, H2R-knockout mice had higher echocardiographic LV fractional shortening, a larger contractility index, a significantly lower LV end-diastolic pressure, and more importantly, markedly lower pulmonary congestion compared with the wild-type mice. Similar results were obtained in wild-type TAC mice treated with H2R blocker famotidine. Histological examinations showed a lower degree of cardiac fibrosis and apoptosis in H2R-knockout mice. H2R activation increased mitochondrial permeability and induced cell apoptosis in cultured cardiomyocytes, and also enhanced the protein expression of calcineurin, nuclear factor of activated T-cell and fibronectin in fibroblasts rather than in cardiomyocytes. These findings indicate that a lack of H2R generates resistance towards heart failure and the process is associated with the inhibition of cardiac fibrosis and apoptosis, adding to the rationale for using H2R blockers to treat patients with CHF.
authors.affiliation: *The State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: *The State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Shen
authors.affiliation: *The State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Xixian
authors.initials: X
authors.lastname: Li
authors.affiliation: *The State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Luo
authors.affiliation: *The State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Wei
authors.affiliation: *The State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Zhang
authors.affiliation: *The State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Shiping
authors.initials: S
authors.lastname: Cao
authors.affiliation: *The State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Huang
authors.affiliation: †The Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Fukushima
authors.affiliation: *The State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Bin
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kitakaze
authors.affiliation: *The State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Dingli
authors.initials: D
authors.lastname: Xu
authors.affiliation: *The State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Yulin
authors.initials: Y
authors.lastname: Liao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D019703:Calcineurin / Q000378:metabolism; D018450:Disease Progression; D005355:Fibrosis / Q000235:genetics; D055786:Gene Knockout Techniques; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006439:Hemodynamics; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D009206:Myocardium / Q000473:pathology*; D010539:Permeability; D011970:Receptors, Histamine H2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D011970:Receptors, Histamine H2; D019703:Calcineurin