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Effect of endostatin overexpression on angiotensin II-induced cardiac hypertrophy in rats
You-Jin Dai1, Jue-Xiao Gong2, Rong Bian3
1Key Laboratory of Model Animal Research, Animal Core Facility of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
Background:
Endostatin, a biologically active fragment of collagen XVIII, has been observed in patients with ischemic heart disease. The aim of the present study was to investigate whether endostatin overexpression could attenuate cardiac hypertrophy by inhibiting the cyclic adenosine monophosphate-protein kinase A (cAMP-PKA) signaling pathway.
Methods:
This study was examined in vivo in rats and in vitro in primary neonatal rat cardiomyocytes treated with angiotensin (Ang) II to model cardiac hypertrophy. Twenty-four male Sprague-Dawley rats were randomized into adenovirus (Ad)-green fluorescent protein, Ang II, Ad-endostatin, and Ang II + Ad-endostatin groups (n = 6 in each group). Four weeks later, all the rats were weighed and sacrificed after transthoracic echocardiography. Cardiac function was evaluated by transthoracic echocardiography, cardiomyocyte size was evaluated by hematoxylin-eosin staining. Levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were evaluated by quantitative reverse-transcription polymerase chain reaction or Western blotting, PKA level was evaluated by Western blotting, and cAMP level was evaluated by enzyme-linked immunosorbent assay. Statistical significance among multiple groups was evaluated by one-way analysis of variance.
Results:
Endostatin overexpression reduced the increases in left ventricle (LV) mass (P = 0.0063), LV mass/body weight (BW) (P = 0.0013), interventricular septal thickness (IVS) in diastole (P = 0.0013), IVS in systole (P = 0.0056), left ventricular posterior wall thickness (LVPW) in diastole (P = 0.0291), LVPW in systole (P = 0.0080), heart weight (HW) (P = 0.0138), HW/BW (P = 0.0001), and HW/tibial length (P = 0.0372) in Ang II-treated rats. In addition, endostatin overexpression reduced cardiomyocyte cross-sectional area expansion, and reduced the levels of ANP and BNP in Ang II-treated rats (P = 0.0251 and 0.0477 for messenger RNA [mRNA]), and primary neonatal rat cardiomyocytes (P = 0.0188 and P = 0.0024 for mRNA; P = 0.0023 and 0.0013 for protein, respectively). Additionally, endostatin overexpression reduced the increase of cAMP (P = 0.0054) and PKA (P = 0.0328) levels in cardiomyocytes treated with Ang II. Treatment with cAMP reversed the effects of endostatin overexpression on ANP (P = 0.0263) and BNP (P = 0.0322) levels in cardiomyocytes induced by Ang II.
Conclusion:
Endostatin overexpression could alleviate cardiac hypertrophy by inhibiting the cAMP-PKA signaling pathway.
Insights
Endostatin overexpression reduced cardiac hypertrophy in rats by inhibiting the cyclic adenosine monophosphate-protein kinase A (cAMP-PKA) signaling pathway. This suggests endostatin as a potential therapeutic target for heart disease.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Biochemistry
Background:
- Endostatin, a collagen XVIII fragment, is found in patients with ischemic heart disease.
- Cardiac hypertrophy is a significant risk factor for heart failure.
- The cyclic adenosine monophosphate-protein kinase A (cAMP-PKA) pathway plays a role in cardiac remodeling.
Purpose of the Study:
- To investigate the effect of endostatin overexpression on cardiac hypertrophy.
- To determine if endostatin can attenuate cardiac hypertrophy by inhibiting the cAMP-PKA signaling pathway.
Main Methods:
- In vivo study using angiotensin II-induced cardiac hypertrophy in rats.
- In vitro study using primary neonatal rat cardiomyocytes treated with angiotensin II.
- Adenovirus-mediated endostatin overexpression.
- Assessment of cardiac function, cardiomyocyte size, ANP/BNP levels, and cAMP-PKA pathway activity.
Main Results:
- Endostatin overexpression significantly reduced cardiac hypertrophy markers, including left ventricle mass and cardiomyocyte size.
- Endostatin overexpression decreased the expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP).
- Endostatin overexpression inhibited the cAMP-PKA signaling pathway, and cAMP administration reversed endostatin's effects on ANP and BNP.
Conclusions:
- Endostatin overexpression alleviates cardiac hypertrophy.
- The mechanism involves the inhibition of the cAMP-PKA signaling pathway.
- Endostatin shows potential as a therapeutic agent for cardiac hypertrophy.
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