Myocyte membrane and microdomain modifications in diabetes: determinants of ischemic tolerance and cardioprotection
Russell et al. Cardiovasc Diabetol
Myocyte membrane and microdomain modifications in diabetes: determinants of ischemic tolerance and cardioprotection
Jake Russell
Eugene F. Du Toit
Jason N. Peart
Hemal H. Patel
John P. Headrick 0
0 School of Medical Science, Griffith University , Southport, QLD 4217 , Australia
Cardiovascular disease, predominantly ischemic heart disease (IHD), is the leading cause of death in diabetes mellitus (DM). In addition to eliciting cardiomyopathy, DM induces a 'wicked triumvirate': (i) increasing the risk and incidence of IHD and myocardial ischemia; (ii) decreasing myocardial tolerance to ischemia-reperfusion (I-R) injury; and (iii) inhibiting or eliminating responses to cardioprotective stimuli. Changes in ischemic tolerance and cardioprotective signaling may contribute to substantially higher mortality and morbidity following ischemic insult in DM patients. Among the diverse mechanisms implicated in diabetic impairment of ischemic tolerance and cardioprotection, changes in sarcolemmal makeup may play an overarching role and are considered in detail in the current review. Observations predominantly in animal models reveal DM-dependent changes in membrane lipid composition (cholesterol and triglyceride accumulation, fatty acid saturation vs. reduced desaturation, phospholipid remodeling) that contribute to modulation of caveolar domains, gap junctions and T-tubules. These modifications influence sarcolemmal biophysical properties, receptor and phospholipid signaling, ion channel and transporter functions, contributing to contractile and electrophysiological dysfunction, cardiomyopathy, ischemic intolerance and suppression of protective signaling. A better understanding of these sarcolemmal abnormalities in types I and II DM (T1DM, T2DM) can inform approaches to limiting cardiomyopathy, associated IHD and their consequences. Key knowledge gaps include details of sarcolemmal changes in models of T2DM, temporal patterns of lipid, microdomain and T-tubule changes during disease development, and the precise impacts of these diverse sarcolemmal modifications. Importantly, exercise, dietary, pharmacological and gene approaches have potential for improving sarcolemmal makeup, and thus myocyte function and stress-resistance in this ubiquitous metabolic disorder.
Caveolae; Cardioprotection; Cholesterol; Diabetes; Fatty acids; Glucose transport; Infarction; Phospholipids
Diabetes impacts myocardial ischemic tolerance and cardioprotection
Clinical evidence indicates DM sensitizes human hearts
to I–R injury [
1, 2
], which is generally consistent with
experimental findings in animal models, though
conflicting observations arise. Compounding the problem of
infarct intolerance, DM may also render hearts broadly
refractory to established cardioprotective stimuli that
include ischemic pre- and post-conditioning (direct
or remote) and protective G protein-coupled receptor
(GPCR) agonism, together with the anti-infarct effects
of ATP-gated K+ channel (KATP) openers, anesthetics,
phosphodiesterase-5 (PDE-5) inhibition and heat shock
activation [
3–6
]. Thus, while elusive cardioprotective
therapies [
6–8
] are of particular value in the high-risk
DM population, implementation appears an even greater
challenge in this cohort. Prevalence of DM and
insulinresistance in those suffering IHD may in turn contribute
to poor translation of experimental cardioprotection in
these patients. Relatively few studies specifically address
the conundrum of I–R sensitivity and cardioprotective
insensitivity in DM [
6
]. Investigations to date implicate
a diversity of mechanisms extending beyond
fundamental alterations in glucose and lipid metabolism, including
associated glycation/glycosylation [
9
], oxidative stress
[
10, 11
], abnormal survival kinase signaling [
12–14
] and
exosome dysfunction [15], excessive
ubiquitin–proteasome system activity [
16
], suppression of sirtuin-1
expression [
17
], and changes in miRNA expression [
18
], among
others. Considerable attention has focused on
mitochondrial dysfunction, including shifts in quality
control mechanisms (mitophagy, fission/fusion), as a point
of convergence in the complex pathogenesis of diabetic
cardiomyopathy [
10, 19, 20
]. However, the sarcolemma
is also a critical though under-appreciated nexus,
influencing DM progression and its impacts [
21
]. Indeed,
transcriptomic profiling indicates that the largest group
of diabetes-modified cardiac genes encode membrane/
plasma membrane components [
22
], consistent with
more recent studies identifying DM-dependent changes
in transcripts for membrane and structural proteins,
sarcolemmal receptors and ion channels [
23
]. Transporters
for glucose and fatty acids, ion channels and
exchangers, and receptor systems governing insulin responses,
inflammation, mitochondrial quality control, and cell
stress, growth and death are all located within the
sarcolemma, while mitochondrial fun (...truncated)