Abstract
BackgroundThe clinical problem of a “pure volume overload” as in isolated mitral or aortic regurgitation currently has no documented medical therapy that attenuates collagen loss and the resultant left ventricular (LV) dilatation and failure. Here, we identify a potential mechanism related to upregulation of the kallikrein-kinin system in the volume overload of aortocaval fistula (ACF) in the rat.Methodology/Principal FindingsLV interstitial fluid (ISF) collection, hemodynamics, and echocardiography were performed in age-matched shams and 4 and 15 wk ACF rats. ACF rats had LV dilatation and a 2-fold increase in LV end-diastolic pressure, along with increases in LV ISF bradykinin, myocardial kallikrein and bradykinin type-2 receptor (BK2R) mRNA expression. Mast cell numbers were increased and interstitial collagen was decreased at 4 and 15 wk ACF, despite increases in LV ACE and chymase activities. Treatment with the kallikrein inhibitor aprotinin preserved interstitial collagen, prevented the increase in mast cells, and improved LV systolic function at 4 wk ACF. To establish a cause and effect between ISF bradykinin and mast cell-mediated collagen loss, direct LV interstitial bradykinin infusion in vivo for 24 hrs produced a 2-fold increase in mast cell numbers and a 30% decrease in interstitial collagen, which were prevented by BK2R antagonist. To further connect myocardial stretch with cellular kallikrein-kinin system upregulation, 24 hrs cyclic stretch of adult cardiomyocytes and fibroblasts produced increased kallikrein, BK2R mRNA expressions, bradykinin protein and gelatinase activity, which were all decreased by the kallikrein inhibitor-aprotinin.Conclusions/SignificanceA pure volume overload is associated with upregulation of the kallikrein-kinin system and ISF bradykinin, which mediates mast cell infiltration, extracellular matrix loss, and LV dysfunction–all of which are improved by kallikrein inhibition. The current investigation provides important new insights into future potential medical therapies for the volume overload of aortic and mitral regurgitation.
Highlights
There is currently no medical therapy that attenuates the eccentric left ventricular (LV) remodeling in the clinical pure volume overload of mitral or aortic regurgitation [1,2,3]
The potential pathophysioloic role of bradykinin in an isolated volume overload is of particular interest because we have previously demonstrated an increase in interstitial fluid (ISF) of bradykinin [5] and significant attenuation of LV dilatation with bradykinin type 2 receptor (BK2) in the early phase of aortocaval fistula (ACF) in the rat [4,5]
We show how the increase in the LV kallikrein-kinin system expression can explain interstitial collagen loss and inflammatory cell infiltration that have been central to the pathophysiology of LV dilatation in a chronic pure volume overload
Summary
There is currently no medical therapy that attenuates the eccentric left ventricular (LV) remodeling in the clinical pure volume overload of mitral or aortic regurgitation [1,2,3]. The pure volume overload of aortocaval fistula (ACF) in the rat causes a LV stretch stimulus without an increase in LV pressure due to the arterial-venous shunt. It is tempting to speculate that ACE inhibition, which decreases angiotensin II and increases bradykinin, exacerbates collagen loss and fails to prevent LV dilatation in a pure volume overload. The clinical problem of a ‘‘pure volume overload’’ as in isolated mitral or aortic regurgitation currently has no documented medical therapy that attenuates collagen loss and the resultant left ventricular (LV) dilatation and failure. We identify a potential mechanism related to upregulation of the kallikrein-kinin system in the volume overload of aortocaval fistula (ACF) in the rat
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