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. 2011 Apr;300(4):H1501-9.
doi: 10.1152/ajpheart.00636.2010. Epub 2011 Jan 7.

Myocardial transfection with naked DNA plasmid encoding hepatocyte growth factor prevents the progression of heart failure in dogs

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Myocardial transfection with naked DNA plasmid encoding hepatocyte growth factor prevents the progression of heart failure in dogs

Sharad Rastogi et al. Am J Physiol Heart Circ Physiol. 2011 Apr.

Abstract

This study examined the effects of localized intramyocardial injections of hepatocyte growth factor (HGF) naked DNA plasmid on the progression of left ventricular (LV) dysfunction and remodeling in dogs with moderate heart failure (HF). Twenty-one dogs with intracoronary microembolization-induced HF [LV ejection fraction (EF) = 35-40%] were randomized into three treatment groups, namely, high-dose HGF plasmid (4.0 mg, n = 7), low-dose HGF plasmid (0.4 mg, n = 7), and sham-operated controls treated with normal saline (n = 7). A total of 10-15 injections of HGF plasmid or saline were made directly into the anterior wall of LV. LV EF and end-systolic volume (ESV) were measured before randomization (pretreatment) and at the end of 3 mo of follow-up (posttreatment). Treatment effect (Δ) was calculated as the change from pre- to posttreatment. Protein expression of sarcoplasmic reticulum (SR) Ca(2+)-cycling proteins was determined in LV tissue obtained from the sites of HGF injection and remote areas. Low-dose HGF attenuated the decline in EF (ΔEF: -3 ± 1 vs. -8 ± 1%, P < 0.05) and the increase in ESV (ΔESV: 6 ± 2 vs. 10 ± 1 ml, P < 0.05) seen in control sham-operated dogs, whereas high-dose HGF significantly increased EF (ΔEF: 4 ± 1 vs. -8 ± 1%, P < 0.05) and prevented the increase in ΔESV (ESV: -1 ± 1 vs. 10 ± 1 ml, P < 0.05) compared with control dogs. Treatment with high- and low-dose HGF improved the expression of the SR Ca(2+)-cycling proteins compared with controls. In conclusion, regional intramyocardial injections of HGF naked DNA plasmid improve regional and global LV function and prevent progressive LV remodeling.

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Figures

Fig. 1.
Fig. 1.
Bar graphs depicting the levels of mRNA expression (A) and protein (B) of hepatocyte growth factor (HGF) in the anterior, lateral, and posterior LV wall basal, midwall (mid), and apical segments (apex) of a normal dog 2 wk after injections of HGF DNA plasmid in the anterior wall only. du, Densitometric units.
Fig. 2.
Fig. 2.
Scatter plots showing the relationship between the change (Δ) in heart rate and the change in left ventricular ejection fraction (top) and the change in fractional area of shortening (bottom ) for the control group, low-dose HGF (LD-HGF) group, and high-dose HGF (HD-HGF) group. P values indicate probability from linear regression analysis.
Fig. 3.
Fig. 3.
Representative micrographs from left ventricular anterior wall sections stained with Griffonia simplicifolia lectin from a sham-operated control dog (A) and from the left ventricular anterior wall of a dog treated with HD-HGF (B). Cardiomyocytes (M) appear as large, nearly black bodies outlined by light green interstitial space. Capillary profiles (C) appear as light white-green bodies.
Fig. 4.
Fig. 4.
Representative bands showing protein expression of calsequestrin (CSQ), sarcoplasmic reticulum Ca2+-ATPase-2a (SERCA-2a), phospholamban (PLB), ryanodine receptor (RyR), phosphorylated-PLB at serine 16 (P-PLB16) and threonine 17 (P-PLB17), and phosphorylated-RyR (P-RyR) in LV myocardium of normal dogs (NL), control heart failure dogs, and dogs treated with LD-HGF or HD-HGF.

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