Intramyocardial Injection of Fibroblast Growth Factor-2 Plus Heparin Suppresses Cardiac Failure Progression in Rats With Hypertensive Heart Disease

Abstract

SUMMARYA reduction of coronary flow reserve has been reported in patients with hypertensive heart disease (HHD), which suggests that myocardial ischemia may contribute to the progression to cardiac failure in HHD. Therefore, we evaluated whether fibroblast growth factor (FGF)-2 and/or heparin, which induce angiogenesis, may affect cardiac function in the setting of HHD.We used Dahl salt sensitive (DS) rats as an HHD model. Direct intramyocardial injection of 100 µg of FGF-2 plus 1.28 µg of heparin (n = 6), 100 µg of FGF-2 (n = 6), 1.28 µg of heparin (n = 6) or saline (n = 6) were performed in 9-week-old rats. Echocardiography was performed to evaluate cardiac function at 9, 11, and 13 weeks of age. Plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) concentrations were measured at 8 and 13 weeks of age. DS rats were killed 4 weeks after myocardial injection (at 13 weeks of age), and myocardial capillary density was assessed by von Willebrand factor staining. Injection of FGF-2 plus heparin significantly decreased left ventricular end-diastolic diameter (P < 0.0001) and left ventricular end-systolic diameter (P < 0.0001), significantly improved the reduction of left ventricular fractional shortening (P = 0.0005), significantly decreased plasma ANP (P < 0.0001) and BNP (P = 0.016) concentrations, and significantly increased myocardial capillary density (P = 0.0002) compared with injection of saline. These findings indicate that intramyocardial injection of FGF-2 plus heparin suppresses the progression of cardiac failure in DS rats. FGF-2 plus heparin administration may be a new therapeutic strategy for the treatment of HHD. (Int Heart J 2005; 46: 289-301) Key words: Heart failure, Fibroblast growth factor-2, Hypertensive heart disease, Angiogenesis, Dahl salt sensitive rat SUSTAINED hypertension induces left ventricular hypertrophy 1) and disturbs the coronary circulation.

Angiogenic Endothelial Cell Signaling in Cardiac Hypertrophy and Heart Failure

“…Studies also revealed differential effects of high and low molecular weight isoforms of FGF2 on cardiac hypertrophy, fibrosis and inflammation (143). Intramyocardial injection of FGF2 (plus heparin) in rats with hypertension-induced cardiac hypertrophy was associated with significant improvements in systolic pump function and ventricular dilation, as well as increased myocardial capillary density (144). Other members of the FGF growth factor family (e.g., acidic FGF or FGF1) may also promote angiogenesis (145) and have been shown to be overexpressed in hearts of patients with dilated cardiomyopathy (146), but their role in cardiac hypertrophy has not been directly examined experimentally.…”

Basic fibroblast growth factor inhibits ventricular remodeling in Dahl salt-sensitive hypertensive rats

“…Our colleagues demonstrated that a single intramyocardial injection of bFGF induces an increase in capillary and arteriolar density, which subsequently suppresses the progression of cardiac failure in Dahl salt-sensitive rats with hypertensive heart disease (HHD) [4]. Hypertension contributes to left ventricular hypertrophy (LVH) and plays an etiological role in left ventricular remodeling [5], which involves disruption of the supporting structure, cell slippage, myocyte hypertrophy, and interstitial fibrosis [6].…”

Inhibition of dipeptidyl peptidase-4 ameliorates cardiac ischemia and systolic dysfunction by up-regulating the FGF-2/EGR-1 pathway

“…FGF-2 is processed into its mature form by truncation of 9 amino acids at the NH2-terminal (MAASGITSLPALPEDGG,), and there is another putative truncation site for DPP-4 following PALPEDGG,. It was reported that FGF-2 has a cardioprotective role by promoting angiogenesis in cardiac tissue [ 45 ], suggesting that suppression of FGF-2-induced angiogenesis by DPP-4 may be one of the pathologic changes mediated by this molecule.…”