Abstract: TH-PO196
Novel Role of BK-Channel Activation in Ameliorating Cardiac Fibrosis in the Ischemia-Reperfusion (IR)-Induced Heart Failure Mouse Model
Session Information
- Hypertension and CVD: Basic Research Findings
October 24, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1601 Hypertension and CVD: Basic
Authors
- Luo, Xiaomao, Emory University, Atlanta, Georgia, United States
- Liu, Zimeng, Emory University, Atlanta, Georgia, United States
- Bian, Shuyang, Emory University, Atlanta, Georgia, United States
- Hassounah, Faten, Emory University, Atlanta, Georgia, United States
- Yue, Qiang, Emory University, Atlanta, Georgia, United States
- Wang, Xiaonan H., Emory University, Atlanta, Georgia, United States
- Cai, Hui, Emory University, Atlanta, Georgia, United States
Background
Ischemic heart disease poses a significant global health challenge, impacting over 244 million adults worldwide. Our previous study has shown that the Big Potassium (BK) ion channel prevents renal fibrosis. However, it remains unclear whether BK channel has anti-fibrotic role in the heart.
Methods
Heart failure model was induced by Ischemic-Reperfusion (I/R) surgery in C57/BL6 mice. To upregulation of BKα, BMS-191011 (10 mg/kg BW) was given by IP injection daily for 8 weeks. Single channel recordings were used to analyze the activation of BKα channel. Cultured H9C2 cardiac myoblasts were used to assess the impact of BK opener (NS1916 10mM) on fibrosis markers and oxidative stress. Hydrogen peroxide (H2O2), superoxide and superoxide dismutase (SOD) were deternubed by Amplex Red Hydrogen Peroxide Kit, Dihydroethidium (DHE) Assay and colorimetric activity kit, respectively. The mRNA expression of BKα and inflammatory cytokines were assayed by qPCR.
Results
The expression of BKα mRNA and protein was decreased while cardiac fibrosis increased in the hearts of I/R mice. Fibronectin, vimentin, and αSMA were significantly elevated in I/R hearts; conversely, BMS treatment attenuated the levels of these proteins.
Echocardiogram revealed an increase in left ventricular end-diastolic dimension in I/R mice, which returned to normal following BK opener treatment. Ejection fraction also improved with this treatment. In addition, the activation of BKα channel prevented I/R-induced upregulation of inflammatory cytokines, such as TNFα, IL-1β, TGFβ and phospho-smad 2/3 in the heart of I/R mice. Single channel recordings found that TGFβ inhibited BKα activity. In H9C2 cells TGFβ increased fibronectin and collagen I production, while BKα openers (NS1619) limited the TGFβ -induced increase in both proteins. TGFβ also significantly increased H2O2 and superoxide production in H9C2 cells. Activation of BKα channel abolished this effect along with reversing TGFβ-induced down-regulation of SOD production.
Conclusion
Our findings suggest that BK channel activation has a protective role in I/R-induced chronic heart failure by reducing cardiac fibrosis and improving cardiac function, which provide the potential therapeutic target of BK in treating fibrosis and improving heart function following cardiac I/R.
Funding
- Veterans Affairs Support