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Loss of IP3R-BKCa Coupling Is Involved in Vascular Remodeling in Spontaneously Hypertensive Rats
Sayeman Islam Niloy1, Yue Shen1, Lirong Guo2
1Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA.
Insights
Loss of coupling between large-conductance calcium-sensitive potassium (BKCa) channels and inositol 1,4,5-trisphosphate receptors (IP3R) in vascular smooth muscle cells contributes to hypertension-induced vascular remodeling and smooth muscle cell proliferation.
Area of Science:
- Cardiovascular Physiology
- Molecular Biology
- Hypertension Research
Background:
- Vascular remodeling in hypertension is complex and involves vascular smooth muscle cell (VSMC) proliferation.
- The precise mechanisms linking large-conductance calcium-sensitive potassium (BKCa) channels to hypertension-related vascular changes remain unclear.
- Interactions between BKCa channels and inositol 1,4,5-trisphosphate receptors (IP3R) are implicated in cellular signaling but their role in hypertension is not fully understood.
Purpose of the Study:
- To investigate the role of BKCa channel and IP3R interaction in vascular smooth muscle cells during hypertension.
- To determine if impaired IP3R-BKCa coupling contributes to VSMC proliferation and vascular remodeling in hypertensive rats.
- To evaluate the therapeutic potential of targeting IP3R-BKCa coupling in hypertension.
Main Methods:
- Comparison of VSMC proliferation and vascular morphology between hypertensive and normotensive rats.
- Electrophysiological recordings (patch clamp) to assess BKCa channel activity and IP3R-BKCa coupling.
- Western blot analysis and co-immunoprecipitation to examine protein expression and interaction between BKCa and IP3R.
- Pharmacological manipulation using IP3R agonist (Adenophostin A) and BKCa opener (NS1619).
- Genetic manipulation using junctophilin-2 shRNA to disrupt IP3R-BKCa coupling.
Main Results:
- BKCa channel function was similar in VSMCs from hypertensive and normotensive rats under basal conditions.
- IP3R-BKCa coupling, assessed by Adenophostin A-induced currents, was significantly attenuated in VSMCs from hypertensive rats, indicating functional decoupling.
- Co-immunoprecipitation revealed a reduced association between BKCa and IP3R proteins in hypertensive VSMCs.
- Disruption of IP3R-BKCa coupling enhanced Ang II-induced VSMC proliferation.
- BKCa channel opening with NS1619 attenuated vascular hypertrophy in hypertensive rats, suggesting reversal of dysfunction.
Conclusions:
- Loss of IP3R-BKCa coupling in VSMCs leads to BKCa channel dysfunction.
- Impaired IP3R-BKCa coupling enhances VSMC proliferation, contributing to vascular hypertrophy in hypertension.
- Targeting IP3R-BKCa coupling represents a potential therapeutic strategy for managing hypertension-related vascular complications.
Abstract:
Mechanisms by which BKCa (large-conductance calcium-sensitive potassium) channels are involved in vascular remodeling in hypertension are not fully understood. Vascular smooth muscle cell (VSMC) proliferation and vascular morphology were compared between hypertensive and normotensive rats. BKCa channel activity, protein expression, and interaction with IP3R (inositol 1,4,5-trisphosphate receptor) were examined using patch clamp, Western blot analysis, and coimmunoprecipitation. On inside-out patches of VSMCs, the Ca2+-sensitivity and voltage-dependence of BKCa channels were similar between hypertensive and normotensive rats. In whole-cell patch clamp configuration, treatment of cells with the IP3R agonist, Adenophostin A (AdA), significantly increased BKCa channel currents in VSMCs of both strains of rats, suggesting IP3R-BKCa coupling; however, the AdA-induced increases in BKCa currents were attenuated in VSMCs of hypertensive rats, indicating possible IP3R-BKCa decoupling, causing BKCa dysfunction. Co-immunoprecipitation and Western blot analysis demonstrated that BKCa and IP3R proteins were associated together in VSMCs; however, the association of BKCa and IP3R proteins was dramatically reduced in VSMCs of hypertensive rats. Genetic disruption of IP3R-BKCa coupling using junctophilin-2 shRNA dramatically augmented Ang II-induced proliferation in VSMCs of normotensive rats. Subcutaneous infusion of NS1619, a BKCa opener, to reverse BKCa dysfunction caused by IP3R-BKCa decoupling significantly attenuated vascular hypertrophy in hypertensive rats. In summary, the data from this study demonstrate that loss of IP3R-BKCa coupling in VSMCs induces BKCa channel dysfunction, enhances VSMC proliferation, and thus, may contribute to vascular hypertrophy in hypertension.
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