Disruption of histamine H2 receptor slows heart failure progression through reducing myocardial apoptosis and fibrosis.

Clin Sci (Lond) 2014 Oct;127(7):435-48

*The State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1042/CS20130716DOI Listing
October 2014
5 Reads

Publication Analysis

Top Keywords

heart failure
12
h2r-knockout mice
12
cardiac fibrosis
8
mice wild-type
8
apoptosis fibrosis
8
mechanisms involved
8
h2r activation
8
histamine receptor
8
influences h2r
8
fibrosis apoptosis
8
h2r
7
fibrosis
5
apoptosis
5
mice
5
mice higher
4
fibronectin fibroblasts
4
higher echocardiographic
4
fibroblasts cardiomyocytes
4
weeks h2r-knockout
4
murine hearts
4

References

(Supplied by CrossRef)

Balakumar P et al.
Basic Clin. Pharmacol. Toxicol. 2008

Dvorak A et al.
N. Engl. J. Med. 1986

Similar Publications