Endostatin Overexpression Reduces Angiotensin II-Induced Cardiac Hypertrophy in Rats by Inhibiting cAMP-PKA Signaling
Cardiovascular diseases are the leading cause of death globally, with cardiac hypertrophy—an enlargement of heart muscle cells in response to stress like high blood pressure or hormone imbalances—serving as a major precursor to heart failure. A 2019 study from researchers at Nanjing Medical University and affiliated hospitals in China reveals a promising role for endostatin, a naturally occurring fragment of collagen XVIII, in slowing this damaging process.
The team, led by You-Jin Dai (Key Laboratory of Model Animal Research, Nanjing Medical University), Jue-Xiao Gong (Department of Cardiology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine), and Rong Bian (Department of Rehabilitation, First Affiliated Hospital of Nanjing Medical University), set out to test whether increasing endostatin levels could reduce cardiac hypertrophy caused by angiotensin II (Ang II)—a hormone linked to high blood pressure and heart remodeling. Their work, published in the Chinese Medical Journal, combines rat models and lab-grown heart cells to uncover a key molecular pathway: the cyclic adenosine monophosphate-protein kinase A (cAMP-PKA) system.
How the Study Worked
The researchers used 24 male Sprague-Dawley rats, divided into four groups:
- Control: Treated with a “empty” adenovirus (Ad-GFP) and saline.
- Ang II: Given Ang II via mini-osmotic pumps to induce hypertrophy.
- Endostatin: Treated with an endostatin-expressing adenovirus (Ad-endostatin) and saline.
- Combination: Given both Ang II and Ad-endostatin.
After four weeks, the team measured cardiac function with transthoracic echocardiography, analyzed heart tissue with hematoxylin-eosin (HE) and Masson staining (to assess cell size and fibrosis), and tested gene/protein levels (like ANP and BNP—markers of cardiac stress) using qRT-PCR and Western blotting. They also repeated key experiments in primary neonatal rat cardiomyocytes (lab-grown heart cells) to confirm findings in a controlled setting.
All procedures were approved by the Experimental Animal Care and Use Committee of Nanjing Medical University and followed NIH guidelines for lab animal welfare.
Key Findings: Endostatin Fights Hypertrophy in Rats and Cells
The results were clear: endostatin overexpression significantly reduced Ang II-induced cardiac damage—both in living rats and isolated heart cells.
In Vivo (Rats):
- Smaller, healthier hearts: Endostatin cut increases in left ventricle (LV) mass, interventricular septal thickness (IVS), and left ventricular posterior wall thickness (LVPW) caused by Ang II. Ratios of heart weight to body weight (HW/BW) and tibial length (HW/TL)—key markers of hypertrophy—also dropped.
- Smaller cells, less stress: HE staining showed endostatin reduced cardiomyocyte size by ~30% compared to Ang II-only rats. Levels of ANP and BNP—proteins released when the heart is overworked—were also lower.
- Less fibrosis: Masson staining revealed endostatin reversed Ang II-induced scarring (fibrosis) in heart tissue—a critical driver of heart failure.
In Vitro (Primary Cardiomyocytes):
- Smaller cells, lower stress: Endostatin reduced Ang II-induced cell enlargement and cut ANP/BNP levels (both mRNA and protein).
- Targeted the cAMP-PKA pathway: Ang II increased cAMP (a signaling molecule) and PKA (a protein kinase) levels—both linked to hypertrophy. Endostatin reversed these increases. When the team added cAMP to cells treated with endostatin and Ang II, the benefits of endostatin vanished—proving the cAMP-PKA pathway is essential to its effects.
Why This Matters for Heart Health
Cardiac hypertrophy is a “double-edged sword”: it starts as the heart’s attempt to compensate for stress (like high blood pressure) but eventually leads to stiffness, reduced function, and heart failure. The cAMP-PKA pathway is a known player in this process—when activated, it drives cell growth and stress responses in heart muscle.
Previous research had linked high blood endostatin levels to worse heart failure outcomes, but this study flips the script: controlled overexpression of endostatin (via adenovirus) actually protected against hypertrophy. The team’s finding that endostatin works by blocking cAMP-PKA adds a new layer to our understanding of how this protein acts in the heart.
For example:
- A 1997 study in Cell first identified endostatin as an angiogenesis inhibitor, but this work shows it has direct effects on heart muscle cells.
- A 2013 study in Circulation Research found that blocking PKA prevents hypertrophy in mice—here, endostatin does exactly that.
What’s Next?
While these results are promising, the study has limitations: it used rat models and lab-grown cells, not humans. Future research will need to test whether endostatin-based therapies are safe and effective in people with cardiac hypertrophy.
Still, the findings offer hope for a new approach to treating heart failure—a condition that affects 26 million people globally. By targeting the cAMP-PKA pathway with endostatin, researchers may have found a way to slow or reverse one of the most damaging processes in cardiovascular disease.
Chinese Medical Journal. 2019;132(22):2716–2723. doi.org/10.1097/CM9.0000000000000513
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