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Published on: July 14, 2021
Increased cardiac remodeling in cardiac-specific Flt-1 receptor knockout mice with pressure overload
Liqin Mei1, Yinqing Huang2, Jiafeng Lin2
1Department of Oral Prophylaxis and Hygiene, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, People's Republic of China, 325027.
Abstract:
Vascular endothelial growth factor (VEGF) inhibition has previously been shown to have damaging effects on the heart. Because the role of Flt-1 (a phosphotyrosine kinase receptor for VEGF) in cardiac function and hypertrophy is unclear, we generated mice lacking Flt-1 only in their cardiomyocytes (Flt-1 KO). The hearts from 8- to 10-week-old mice were measured by using echocardiography and histology. No significant differences were seen in fraction shortening, cross-sectional area of cardiomyocytes, and interstitial collagen fraction between littermate controls and KO mice at baseline. To test the hypothesis that Flt-1 is involved in cardiac remodeling, we performed transverse aorta constriction (TAC) by ligating the transverse ascending aorta. Four weeks after TAC, echocardiography of the mice was performed, and the hearts were excised for pathological analysis and Western blotting. No difference in mortality was found between Flt-1 KO mice and controls; however, KO mice showed a greater cardiomyocyte cross-sectional area and interstitial collagen fraction than controls. Western blotting indicated that AKT was activated less in Flt-1 KO hearts after TAC compared with that in control hearts. Thus, Flt-1 deletion in cardiomyocytes increased hypertrophy, fibrosis, and regression of AKT phosphorylation. Our study suggests that Flt-1 plays a critical role in cardiac hypertrophy induced by pressure overload via the activation of AKT, which seems to be cardioprotective.
Insights
Deleting Flt-1 in heart cells worsens cardiac hypertrophy and fibrosis after pressure overload. This suggests Flt-1 activation of AKT is cardioprotective, highlighting its role in preventing heart damage.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Vascular Biology
Background:
- Vascular endothelial growth factor (VEGF) inhibition negatively impacts cardiac health.
- The specific role of Flt-1 (VEGF receptor) in cardiac function and hypertrophy remains largely unknown.
- Understanding Flt-1's cardiomyocyte function is crucial for cardiovascular research.
Purpose of the Study:
- To investigate the role of Flt-1 in cardiomyocytes during cardiac remodeling and hypertrophy.
- To determine the impact of cardiomyocyte-specific Flt-1 deletion on cardiac response to pressure overload.
- To elucidate the signaling pathways, specifically AKT phosphorylation, involved in Flt-1's cardiac effects.
Main Methods:
- Generation of cardiomyocyte-specific Flt-1 knockout (Flt-1 KO) mice.
- Echocardiography and histological analysis of cardiac structure and function at baseline and post-transverse aorta constriction (TAC).
- Western blotting to assess AKT phosphorylation levels in Flt-1 KO and control hearts after TAC.
Main Results:
- Baseline cardiac function and cardiomyocyte size were similar between Flt-1 KO and control mice.
- Following TAC, Flt-1 KO mice exhibited significantly increased cardiomyocyte hypertrophy and interstitial fibrosis compared to controls.
- TAC induced less AKT activation in Flt-1 KO hearts, indicating impaired AKT phosphorylation signaling.
Conclusions:
- Cardiomyocyte-specific Flt-1 deletion exacerbates cardiac hypertrophy and fibrosis in response to pressure overload.
- Flt-1 signaling in cardiomyocytes is critical for mediating AKT activation, which appears to be cardioprotective.
- These findings identify Flt-1 as a key regulator in pressure-induced cardiac remodeling.
