Dissertation/Thesis Abstract

Upregulation of vascular L-type calcium channels in hypertension: Role of β subunits
by Sonkusare, Swapnil, Ph.D., University of Arkansas for Medical Sciences, 2009, 185; 3357551
Abstract (Summary)

The L-type Ca2+ (CaL) channels in the plasma membrane of vascular smooth muscle cells (VSMCs) mediate arterial contraction and vascular tone. These channels consist of a pore-forming α1C subunit and accessory β3 subunits that regulate α1C expression. We hypothesized that the α1C and β3 subunits coordinately upregulate in VSMCs during hypertension resulting in an overabundance of CaL channel complexes, and that the regulatory β3 subunits are required for this response. C57BL/6 mice were infused with angiotensin II (Ang II, 2 ng/g/min) by osmotic minipump for two weeks to establish hypertension. Control normotensive (NT) mice were infused with isotonic saline. Systolic blood pressures (SBP) were 114 ± 3 mm Hg and 170 ± 10 mm Hg in NT and Ang II hypertensive (AHT) mice, respectively. The CaL channel blocker, nifedipine (5 mg/kg, i.p.), restored the elevated SBP to normal in AHT mice but only mildly lowered SBP in NT mice. This finding correlated with an upregulation of the CaL channel α1C and β3 subunits in mesenteric arteries (MA) from AHT mice and increased α 1C and β3 immunofluorescence in the VSMCs. The MA of AHT mice also showed a 5.1-fold higher contractile sensitivity to the CaL channel agonist FPL 64176 and a 1.91-fold increase in CaL channel current in isolated VSMCs. Notably, β3 subunit knockout (β3KO) mice showed less upregulation of vascular α1C and blood pressure elevation in response to Ang II infusion than wild-type (WT) mice. The SBP levels were 145 ± 10 mm Hg (β3KO) and 179 ± 5 mm Hg (WT). These findings suggest that the CaL channels that mediate anomalous vascular tone during hypertension are α1C-β3 heteromultimers, and that the β3 subunit is required for the upregulation of vascular CaL channels in AHT mice. A final set of in vitro studies demonstrated that siRNA knock down of β3 subunits in cultured VSMCs reduces CaL channel current. Similarly, mutant β2 subunits can be employed to reduce the surface expression of CaL channels in HL-1 cardiomyocytes. These results provide proof of principle that limiting the availability of the β subunits represents a therapeutic strategy for reducing CaL channel expression.

Indexing (document details)
Advisor: Rusch, Nancy J.
Commitee:
School: University of Arkansas for Medical Sciences
School Location: United States -- Arkansas
Source: DAI-B 70/04, Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Pharmacology
Keywords: Alpha and beta subunits, Angiotensin II, Calcium channels, Hypertension, Mesenteric arteries
Publication Number: 3357551
ISBN: 9781109148275
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