Role and Mechanism of Lamellar Derived Growth Factor /AKT Pathway in Ventricular Remodeling Induced by Pressure Overload.

Abstract

This study aimed to investigate the role and underlying mechanisms of the platelet-derived growth factor (PDGF)/protein kinase B (AKT) signaling pathway in pressure overload-induced ventricular remodeling. Ventricular remodeling, a critical pathological process in heart failure, is commonly triggered by pressure overload. While PDGF is known to promote cell proliferation and growth, the AKT pathway is crucial for cell growth, survival, and metabolism. However, the specific role of the PDGF/AKT pathway in pressure overload-induced ventricular remodeling remains unclear. Thus, this study aimed to elucidate the precise mechanisms of PDGF/AKT involvement in this process using animal models and cell experiments. 45 female C57BL/6 mice were utilized, randomly divided into three groups: model group (M group, n = 15), control group (C group, n = 15), and experimental group (E group, n = 15). M group mice underwent thoracotomy without aortic constriction (AC). C group mice received phosphate-buffered saline (PBS) and dimethyl sulfoxide (DMSO) treatment following AC surgery. E group mice were treated with the PDGF receptor inhibitor AG1296 and PBS solution after AC surgery. Additionally, 293 T cells were categorized into three groups: PDGF shRNA transfected group (downregulating PDGF expression, D group), PDGF overexpression group (B group), and control group (NV group). Left ventricular end-systolic volume (LVESV) and ejection fraction (FS) of the mice were measured via echocardiography. Western blot analysis was conducted to assess the expression levels of p-AKT and t-AKT in myocardial tissues. Furthermore, myocardial cell area was measured using hematoxylin and eosin (HE) staining and image analysis software. The LVESV in the C group was significantly higher than in the M and E groups (48.32 ± 3.08 mL vs. 18.24 ± 3.19 mL and 25.44 ± 3.12 mL, P < 0.05). The FS in the C group was significantly lower compared to the M and E groups (21.18 ± 2.99% vs. 42.45 ± 3.02% and 26.89 ± 2.54%, P < 0.05). Western blot analysis revealed that p-AKT and t-AKT levels were significantly elevated in the C group and PDGF overexpression group (B group) compared to the M and PDGF shRNA groups (D group) (P < 0.05). HE staining showed a significant increase in myocardial cell cross-sectional area in the C and D groups, with the most pronounced enlargement in the D group (P < 0.05). PDGF facilitates pressure overload-induced ventricular remodeling and myocardial fibrosis. Inhibition of the PDGF/AKT signaling pathway effectively mitigates myocardial cell hypertrophy and ventricular remodeling. These findings offer novel potential targets and therapeutic strategies for the treatment of pressure overload-related heart failure.