Indiana University-Purdue University Indianapolis (IUPUI) / Metabolic syndrome (MetS) affects 1/3 of all Americans and is the clustering of
three or more of the following cardiometabolic risk factors: obesity, hypertension,
dyslipidemia, glucose intolerance, and insulin resistance. MetS drastically increases the
incidence of coronary artery disease (CAD), which is the leading cause of mortality
globally. A cornerstone of CAD is arterial remodeling associated with coronary smooth
muscle (CSM) cytodifferentiation from a contractile phenotype to proliferative and
osteogenic phenotypes. This cytodifferentiation is tightly coupled to changes in
intracellular Ca2+ handling that regulate several key cellular functions, including
contraction, transcription, proliferation, and migration. Our group has recently elucidated
the time course of Ca2+ dysregulation during MetS-induced CAD development. Ca2+
transport mechanisms, including voltage-gated calcium channels, sarcoplasmic reticulum
(SR) Ca2+ store, and sarco-endoplasmic reticulum Ca2+ ATPase (SERCA), are enhanced
in early, mild disease and diminished in late, severe disease in the Ossabaw miniature
swine. Using this well-characterized large animal model, I tested the hypothesis that this
Ca2+ dysregulation pattern occurs in multiple etiologies of CAD, including diabetes and
aging. The fluorescent intracellular Ca2+ ([Ca2+]i) indicator fura-2 was utilized to measure
[Ca2+]i handling in CSM from lean and diseased swine. I found that [Ca2+]i handling is
enhanced in mild disease with minimal CSM phenotypic switching and diminished in
severe disease with greater phenotypic switching, regardless of CAD etiology. We are
confident of the translatability of this research, as the Ca2+ influx, SR Ca2+ store, and
SERCA functional changes in CSM of humans with CAD are similar to those found in Ossabaw swine with MetS. Single-cell RNA sequencing revealed that CSM cells from an
organ culture model of CAD exhibited many different phenotypes, indicating that
phenotypic modulation is not a discreet event, but a continuum. Transcriptomic analysis
revealed differential expression of many genes that are involved in the osteogenic
signaling pathway and in cellular inflammatory responses across phenotypes. These
genes may be another regulatory mechanism common to the different CAD etiologies.
This study is the first to show that CSM Ca2+ dysregulation is common among different
CAD etiologies in a clinically relevant animal model.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/20549 |
| Date | 08 1900 |
| Creators | Badin, Jill Kimberly |
| Contributors | Sturek, Michael S., Evans-Molina, Carmella, Moe, Sharon, Tune, Jonathan D. |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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