Myocyte membrane and microdomain modifications in diabetes: determinants of ischemic tolerance and cardioprotection

Cardiovascular Diabetology, Dec 2017

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.

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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)


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Jake Russell, Eugene F. Toit, Jason N. Peart, Hemal H. Patel, John P. Headrick. Myocyte membrane and microdomain modifications in diabetes: determinants of ischemic tolerance and cardioprotection, Cardiovascular Diabetology, pp. 155,