Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2016 May 27;118(11):1808-29.
doi: 10.1161/CIRCRESAHA.116.306923.

Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes

Manasi S Shah  1 , Michael Brownlee  2
Affiliations
Review

Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes

Manasi S Shah et al. Circ Res. .

Abstract

The clinical correlations linking diabetes mellitus with accelerated atherosclerosis, cardiomyopathy, and increased post-myocardial infarction fatality rates are increasingly understood in mechanistic terms. The multiple mechanisms discussed in this review seem to share a common element: prolonged increases in reactive oxygen species (ROS) production in diabetic cardiovascular cells. Intracellular hyperglycemia causes excessive ROS production. This activates nuclear poly(ADP-ribose) polymerase, which inhibits GAPDH, shunting early glycolytic intermediates into pathogenic signaling pathways. ROS and poly(ADP-ribose) polymerase also reduce sirtuin, PGC-1α, and AMP-activated protein kinase activity. These changes cause decreased mitochondrial biogenesis, increased ROS production, and disturbed circadian clock synchronization of glucose and lipid metabolism. Excessive ROS production also facilitates nuclear transport of proatherogenic transcription factors, increases transcription of the neutrophil enzyme initiating NETosis, peptidylarginine deiminase 4, and activates the NOD-like receptor family, pyrin domain-containing 3 inflammasome. Insulin resistance causes excessive cardiomyocyte ROS production by increasing fatty acid flux and oxidation. This stimulates overexpression of the nuclear receptor PPARα and nuclear translocation of forkhead box O 1, which cause cardiomyopathy. ROS also shift the balance between mitochondrial fusion and fission in favor of increased fission, reducing the metabolic capacity and efficiency of the mitochondrial electron transport chain and ATP synthesis. Mitochondrial oxidative stress also plays a central role in angiotensin II-induced gap junction remodeling and arrhythmogenesis. ROS contribute to sudden death in diabetics after myocardial infarction by increasing post-translational protein modifications, which cause increased ryanodine receptor phosphorylation and downregulation of sarco-endoplasmic reticulum Ca(++)-ATPase transcription. Increased ROS also depress autonomic ganglion synaptic transmission by oxidizing the nAch receptor α3 subunit, potentially contributing to the increased risk of fatal cardiac arrhythmias associated with diabetic cardiac autonomic neuropathy.

Keywords: atherosclerosis; diabetes mellitus; heart failure; insulin resistance; myocardial infarction; reactive oxygen species.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Hyperglycemia-induced myocardial protein modification by O-GlcNAc causes increased intracellular Ca++ and delayed afterpolarizations
Increased intracellular glucose flux provides more substrate for the enzyme O-GlcNAc-transferase (OGT). This increases O-GlcNAc modification of calcium/calmodulin-dependent protein kinase IIδ (CaMKII), causing autonomous CaMKII activation. CaMKII increases intracellular Ca++ by phosphorylating ryanodine receptor 2 (RyR). OGT also modifies transcription complex factors regulating expression of sarcoplasmic reticulum Ca2+-ATPase (SERCA2), reducing SERCA2A expression and contributing toincreased intracellular Ca++. Increased O-GlcNAc modification of these proteins causes delayed afterdepolarizations in cardiomyocytes. PLB, phospholamban.
Figure 2
Figure 2. Four hyperglycemia-induced pathogenic mechanisms are activated by overproduction of ROS
Increased intracellular glucose flux causes mitochondrial overproduction of reactive oxygen species (ROS), which can further amplify ROS production by activating NADPH oxidases and uncoupling eNOS. Stable ROS species diffuse into the nucleus, where they cause DNA damage and activation of poly(ADP ribose) polymerase (PARP). PolyADP-ribosylation of glyceraldehyde-3-dehydrogenase (GAPDH) by PARP reduces GAPDH activity, which causes upstream accumulation of early glycolytic intermediates which are diverted into four pathogenic signaling pathways. AKR1B1, aldose reductase; Gln, glucosamine; GFAT, glutamine fructose-6-phosphate amidotransferase; UDP-GlcNAc, uridine diphosphate N-acetylglucosamine; DHAP, dihydroxyacetone phosphate; DAG, diacylglycerol; PKC, protein kinase C; NF-κB, nuclear factor-κB; AGEs, advanced glycation end-products; RAGE, Receptor for Advanced Glycation Endproducts.
Figure 3
Figure 3. Diabetes reduces Nrf2 protein in diabetic heart
Nuclear erythroid–related factor 2 (Nr2), the master regulator of antioxidant gene expression, associates with the redox-sensitive protein Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1(Keap1), where it is rapidly polyubiquinated by Keap1-associated cullin-3 (Cul3)–RING E2 ubiquitin ligase proteins and degraded by proteasomes. ROS oxidation of critical cysteine thiols of causes release of bound Nrf2 protein. Phosphorylation of Nrf2 by protein kinases such as CK2 help target Nrf2 to the nucleus. Nrf2 forms heterodimers with small Maf proteins which bind to the antioxidant response element (ARE) in its target gene promoters. After export of Nrf2 from the nucleus, cytosolic Nrf2 is phosphorylated by GSK3β. This phosphorylated Nrf2 recognized by β-transducin repeat-containing protein (β-TrCP), a substrate adaptor for the S-phase kinase-associated protein-1 (Skp1)–Cul1–F-box protein (SCF) E3 ubiquitin ligase which targets Nrf2 phosphorylated by GSK3β to the proteosome.
Figure 4
Figure 4. Increased mitochondrial oxidation of glucose or fatty acids activates NFAT-mediated transcription of genes promoting diabetic atherosclerosis and heart failure
Mitochondrial overproduction of ROS causes increased intracellular Ca++, which activates the calcium-activated neutral cysteine protease calpain. Calpain then activates the Ca2+/calmodulin-dependent /CaM) (Ca2+)serine/threonine phosphatase calcineurin. Dephosphorylation facilitates nuclear translocation of the transcription factor Nuclear Factor of Activated T Cells (NFAT). In the nucleus, NFAT interacts with polyADP-ribose polymerase (PARP), which increases NFAT transcriptional activity via NFAT polyADP ribosylation. MCP-1, monocyte chemoattractant protein-1; ICAM-1, Intercellular Adhesion Molecule 1; IL-6, Interleukin-6.
Figure 5
Figure 5. Diabetes increases neutrophil extracellular traps (NETs), priming macrophages for inflammation
Increased ROS increase transcription and activation of peptidylarginine deiminase 4 (PAD4), the enzyme which initiates formation and release of NETs by citrullination of histones. Released NETs prime macrophages to produce pro-IL-1β, which is cleaved to mature pro-inflammatory IL-1β by caspase 1 secreted by macrophages in response to NLRP3 inflammasome activation. Cit, citrullination; αH4R, αhistone 4 Arginine; αH4cit, αhistone 4 with arginine residues converted to citrulline.
Figure 6
Figure 6. NLRP3 inflammasome activation in diabetic atherosclerosis
Intracellular hyperglycemia-induced ROS in monocytes and vascular endothelial cells increases RAGE expression, which heterodimerizes with TLR4. Signaling from this complex causes NFκB-mediated transcription of inactive NOD-like receptor family, pyrin domain-containing 3 (NRLP3), pro-IL-1β, and pro-IL-18. Increased intracellular Ca++ triggers oligomerization of inactive NLRP3, associated with apoptosis-associated speck-like protein (ASC), and pro-caspase-1. This activated inflammsome complex catalyzes the conversion of procaspase-1 to caspase-1, and of pro-IL-1β and pro-IL-18 to mature IL-1β and IL-18. S100A8/12, calgranulin A/B heterodimer ligand for RAGE.
Figure 7
Figure 7. Increased cardiac fatty acid oxidation, ROS formation and cardiolipin remodeling
Insulin resistance-induced increased cardiac β oxidation of free fatty acids (FFA) causes greater H2O2 production than increased glucose oxidation because of increased electron leakage from the electron transfer flavoprotein (ETF) complex. These ROS activate Acyl-CoA:lysocardiolipin acyltransferase 1 (ALCAT1). ALCAT1, located in the mitochondrial associated membrane (MAM) of the ER, which causes pathologic remodeling of cardiolipin from tetra 18:2 cardiolipin to cardiolipin with highly unsaturated fatty acid side chains and cardiolipin deficiency due to oxidative damage. This reduces ETC electron flux, ATP synthesis, and further increases ROS.
Figure 8
Figure 8. Diabetes-induces increased mitochondrial fission
Increased ROS from either excess glucose in vascular cells or fatty acids in cardiomyocytes increases intracellular Ca++. Increased Ca++ activates the calcium-activated neutral cysteine protease calpain, which activates the Ca2+/calmodulin-dependent/CaM) (Ca2+)serine/threonine phosphatase calcineurin. Calcineurin dephosphorylates the GTPase dynamin-related protein 1 (DRP1), which is then recruited from the cytosol to the mitochondrial outer membrane where it binds to four DRP1 receptors- — mitochondrial fission factor (MFF), Mitochondrial dynamics protein of 49 kDa (MID49) and 51 kDa (MID51), and FIS1. Drp1 oligimerization provides the mechanical force to constrict mitochondrial membranes and fragment the organelle (mitochondrial fission). Increased fission causes further increases in ROS production and mitochondrial dysfunction. FIS1, Mitochondrial fission 1 protein.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Gu K, Cowie CC, Harris MI. Mortality in adults with and without diabetes in a national cohort of the U.S. population, 1971–1993. Diabetes Care. 1998;21:1138–45. - PubMed
    1. Virmani R, Burke AP, Kolodgie F. Morphological characteristics of coronary atherosclerosis in diabetes mellitus. The Canadian journal of cardiology. 2006;22(Suppl B):81b–84b. - PMC - PubMed
    1. Gu K, Cowie CC, Harris MI. Diabetes and decline in heart disease mortality in US adults. Jama. 1999;281:1291–7. - PubMed
    1. Burchfield JS, Xie M, Hill JA. Pathological ventricular remodeling: mechanisms: part 1 of 2. Circulation. 2013;128:388–400. - PMC - PubMed
    1. Donahoe SM, Stewart GC, McCabe CH, Mohanavelu S, Murphy SA, Cannon CP, Antman EM. Diabetes and mortality following acute coronary syndromes. Jama. 2007;298:765–75. - PubMed