Abstract 1376: Does an Excess of Cardiotrophin-1 Play a Role in the Transition from Hypertrophy to Failure in the Hypertensive Human Heart?
Increased cardiomyocyte apoptosis has been reported in hypertensive patients with left ventricular hypertrophy (LVH) that develop heart failure (HF). We thus investigated whether the gp130-receptor mediated survival pathway, which protects cardiomyocytes from apoptosis, is depressed in these patients. We performed transvenous endomyocardial biopsies in 52 hypertensives with LVH subdivided into two groups: 28 without HF and 24 with HF. Myocardial gp130 dependent pathway was analyzed by Western blot. Cardiotrophin-1 (CT-1), a cytokine agonist of the gp130 pathway was assessed by Western blot. Apoptosis was assessed by DNA end-labeling (TUNEL), immunostaining for the active form of caspase-3 and PARP cleavage. gp130 was diminished (P<0.05), MAPK p42/44 activation was depressed (P<0.01) and STAT-3 expression (P<0.01) and activation (P<0.01) were diminished in HF hypertensives compared with non-HF hypertensives. CT-1 was increased (P<0.05) in HF hypertensives compared with non-HF hypertensives. In vitro experiments performed in HL-1 murine cardiomyocytes showed that CT-1 decreased (P<0.05) the ratio of gp130 to phosphorylated (at Ser782)-gp130. Cardiomyocyte apoptosis and density were increased (P<0.01) and decreased (P<0.01), respectively, in HF hypertensives compared with non-HF hypertensives. Cardiomy-ocyte apoptosis was inversely correlated with MAPK p42/44 activation (P<0.01), cardiomyocyte density (P<0.01), and left ventricular ejection fraction (P<0.001), and directly correlated with left ventricular end-diastolic diameter (P<0.001) in all hypertensives. These findings suggest that an excessive cardiac generation of CT-1 (likely in response to biomechanical and neurohumoral stress associated with HF) may induce gp130 internalization and degradation thus leading to inhibition of the gp130-mediated survival pathway in cardiomyocytes from HF hypertensives. This alteration may facilitate cardiomyocyte apoptosis which, in turn, may contribute to LV systolic dysfunction and dilatation in HF hypertensives.