Cell-specific role and therapeutic potential of KCa3.1 in atherosclerosis

Pathogenesis of coronary artery disease is complex, with multiple cell types contributing to lesion size
and composition. Acute coronary syndromes are most often associated with rupture of complex,
vulnerable plaques that are otherwise clinically benign. The progression to either a relatively benign,
stable lesion or a rupture-prone, vulnerable plaque has been linked to key lesion characteristics, i.e.
smooth muscle (SM) and collagen content, macrophage infiltration and necrotic core area within the
lesion. The objectives of this proposal are to 1) determine the SM-specific role and underlying
mechanism(s) by which the intermediate conductance, Ca2+-activated K+ channel, KCa3.1 (encoded by
Kcnn4), dictates atherosclerotic lesion formation and composition and 2) determine the translational
potential of clinically approved KCa3.1 inhibitors on lesion development in a large mammal model of
coronary artery disease (CAD). In support, we provide the first genetic evidence of a causal link
between KCa3.1 and lesion size and SM and macrophage recruitment. The overall hypothesis is that
KCa3.1 activation increases migration of SM and macrophages into the intima and contributes to lesion
formation. Conversely, blocking KCa3.1, both by genetic silencing or pharmacologically, will decrease
atherosclerotic lesion size and beneficially alter composition. Aim 1 will determine the contribution of
KCa3.1 in smooth muscle to atherosclerotic lesion formation and composition. Specifically, we will use
SM-specific, inducible KO mice to examine the role of KCa3.1 in determining plaque size, composition
and gene expression. Aim 2 will define both upstream (REST) and downstream (DOCK2) mechanisms
determining KCa3.1 effects on SM and atherosclerosis. We will use genetically modified mice to
examine the role of REST and DOCK2 in mediating SM effects of KCa3.1 on phenotype, proliferation,
migration, plaque size and composition. In addition, we will use RNA sequencing to identify novel
mechanisms of atherosclerosis development by KCa3.1. We will use VSM lineage-tracking in Aim 3 will
use SM lineage-tracking to determine role of SMC-KCa3.1 in mediating SMC intimal to medial migration
and foam cell transdifferentiation during atherosclerotic lesion development. Finally, Aim 4 will
determine the effect of the FDA approved KCa3.1 inhibitor, senicapoc, on atherosclerosis development
in a swine model of CAD. We longitudinally track coronary artery disease progression using
angiography and IVUS in familial hypercholesterolemic (FH) swine to test the ability of KCa3.1 inhibition
with senicapoc, to decrease the size and promote a more favorable composition of coronary lesions.
The long-term goal is to provide the pre-clinical foundation for translating current therapeutic tools and
developing the next generation drugs targeting KCa3.1 and/or downstream signaling to beneficially
manipulate atherosclerotic lesion composition.

Grant Number: 5R01HL151444-04
NIH Institute/Center: NIH
Principal Investigator: DOUGLAS BOWLES