The therapeutic potential of G-CSF in pressure overload induced ventricular reconstruction and heart failure in mice.

In animal models of clinical entities causative of severe right and left ventricular (LV) pressure overload hypertrophy, increased density of the cellular microtubule network, through viscous loading of active myofilaments, causes contractile dysfunction that is normalized by microtubule depolymerization. In this study, 86 male mice were divided into seven groups. The transverse ascending aorta constriction (TAC) in six groups were performed in order to make heart failure model. Mice in each group were injected with G-CSF or/and telmisartan subcutaneously at different time respectively. Results showed that reduction in left ventricular volume and improved function persisted at 2 week, but recurrent dilatation at 4 weeks was associated with a loss of functional improvement. Compared with PBS group, the expression of VEGF protein and HIF-1 mRNA were significantly higher in mice injected with G-CSF or/and telmisartan (P<0.05). The expression of p53 mRNA, myocardial fibrosis and mortality were significantly lower in mice injected with G-CSF or/and telmisartan (P<0.05). It could be concluded that G-CSF can delay the progression of pressure overload induced ventricular reconstruction and heart failure in mice.

Role of Jagged1-Hey1 Signal in Angiotensin II-induced Impairment of Myocardial Angiogenesis.

BACKGROUND: Angiotensin II (Ang II) is a major contributor to the development of heart failure. However, the molecular and cellular mechanisms that underlie this process remain elusive. Inadequate angiogenesis in the myocardium leads to a transition from cardiac hypertrophy to dysfunction, and our previous study showed that Ang II significantly impaired the angiogenesis response. The current study was designed to examine the role of Jagged1-Notch signaling in the effect of Ang II during impaired angiogenesis and cardiac hypertrophy. METHODS: Ang II was subcutaneously infused into 8-week-old male C57BL/6 mice at a dose of 200 ng·kg-1·min-1 for 2 weeks using Alzet micro-osmotic pumps. N-[N-(3, 5-difluorophenacetyl)-L-alanyl]-S-phenylglycine tert-butyl ester (DAPT), a γ-secretase inhibitor, was injected subcutaneously during Ang II infusion at a dose of 10.0 mg·kg-1·d-1. Forty mice were divided into four groups (n = 10 per group): control group; Ang II group, treated with Ang II; DAPT group, treated with DAPT; and Ang II + DAPT group, treated with both Ang II and DAPT. At the end of experiments, myocardial (left ventricle [LV]) tissue from each experimental group was evaluated using immunohistochemistry, Western blotting, and real-time polymerase chain reaction. Data were analyzed using one-way analysis of variance test followed by the least significant difference method or independent samples t-test. RESULTS: Ang II treatment significantly induced cardiac hypertrophy and impaired the angiogenesis response compared to controls, as shown by hematoxylin and eosin (HE) staining and immunohistochemistry for CD31, a vascular marker (P < 0.05 for both). Meanwhile, Jagged1 protein was significantly increased, but gene expression for both Jag1 and Hey1 was decreased in the LV following Ang II treatment, compared to that in controls (relative ratio for Jag1 gene: 0.45 ± 0.13 vs. 0.84 ± 0.15; relative ratio for Hey1 gene: 0.51 ± 0.08 vs. 0.91 ± 0.09; P < 0.05). All these cellular and molecular effects induced by Ang II in the hearts of mice were reduced by DAPT treatment. Interestingly, Ang II stimulated Hey1, a known Notch target, but did not affect the expression of Hey2, another Notch target gene. CONCLUSIONS: A Jagged1-Hey1 signal might mediate the impairment of angiogenesis induced by Ang II during cardiac hypertrophy.