Novel Insights Into the Pathogenesis of Diabetic Cardiomyopathy and Pharmacological Strategies

Abstract

Diabetic cardiomyopathy (DCM) is a severe complication of diabetes developed mainly in poorly controlled patients. In DCM, several clinical manifestations as well as cellular and molecular mechanisms contribute to its phenotype. The production of reactive oxygen species (ROS), chronic low-grade inflammation, mitochondrial dysfunction, autophagic flux inhibition, altered metabolism, dysfunctional insulin signaling, cardiomyocyte hypertrophy, cardiac fibrosis, and increased myocardial cell death are described as the cardinal features involved in the genesis and development of DCM. However, many of these features can be associated with broader cellular processes such as inflammatory signaling, mitochondrial alterations, and autophagic flux inhibition. In this review, these mechanisms are critically discussed, highlighting the latest evidence and their contribution to the pathogenesis of DCM and their potential as pharmacological targets.

Keywords: cardiomyopathy; diabetes; heart; inflammation; mitochondria; mitophagy; pyroptosis.

Figure 1

Novel inflammatory signaling pathways implicated in diabetic cardiomyopathy (DCM) pathogenesis and its possible pharmacological interventions. Inflammatory signaling has been proposed to be responsible for the development of DCM. It is activated by different pathways, including: (A) nuclear factor-kappa b (NF-κB) signaling activated by toll-like receptor 2 (TLR2), TLR4, and myeloid differentiation 2 (MD2)/TLR4 complex, (B) oxidative stress-induced autophagy, (C) oxidative stress, (D) activation of the NLR by pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). Moreover, some non-coding RNAs are described to (E) positively or (F) negatively regulate the inflammasome NLPR3. On the other hand, possible therapeutical strategies attenuating inflammatory signaling are illustrated as follows: (G) TLR2 depletion using siRNA TLR2 or TLR2-KO. (H) TLR4 depletion using siRNA TLR4 or TLR4-KO, TLR4 antagonist Rhodobacter sphaeroides LPS (Rs-LPS) and TLR4 blocker TAK242 and viral inhibitory peptide (VIPER), (I) decreasing NLRP3 by vaspin in an autophagy-dependent mechanism, (J) the inhibition of NLRP3 by metformin in an AMPK/mTOR-dependent manner, and (K) c-Jun N-terminal kinase (JNK) and spleen tyrosine kinase (SYK) inhibitor, melatonin, gypenosides (Gps), atorvastatin, SLGT2 inhibitor + P2Y12R antagonist, and SGLT2 inhibitor + DPP4 inhibitor.

Figure 2

Novel differences between healthy and DCM mitochondrial function and its pharmacological targets. (A) Normally, the mitochondria used glucose, lipids, and ketones as the fuel to obtain adenosine triphosphate (ATP) in the oxidative phosphorylation (OXPHOS) according to the necessities of the cell, (B) but in DCM, there is an excess of available fuels, increasing glucose, palmitate, and advanced glycation end products (AGEs) that affect the flexibility in substrate use by the mitochondria triggering mitochondrial dysfunction. This process is evidenced by a lower mitochondrial membrane potential, decreased production of ATP by OXPHOS, and increased reactive oxygen species (ROS). The mechanisms of mitochondrial deterioration in DCM are illustrated as follows: (C) the decrease in OXPHOS activity by O-GlcNAcylation (OGA), (D) the upregulation of calpains in the diabetic heart, (E) the abnormal production of mitochondrial ROS, (F) the production of cytosolic ROS by an increase in the expression of NADPH oxidases 4 (NOX4) indirectly regulated by FOXO1, and (G) the downregulation of TOM70 in the diabetic heart. Thus, therapeutic strategies aiming to improve a mitochondrial function are represented as follows: (H,I) the overexpression of β-hydroxybutyrate-dehydrogenase (BDH1) and Canagliflozin or Empagliflozin to increase the use of ketones, (J) dominant-negative for OGA (O-GlcNAcase DN), (K) inhibition of calpain activity by calpastatin (endogenous calpain inhibitor) or capn4 knockout, and (L) micro-RNA 30c (miR-30c) reduces the proliferator-activated receptor alpha (PPARα) coactivator PGC-1β.

Figure 3

Novel regulations of cellular catabolic pathways in DCM and its therapeutical strategies. The autophagic inhibition plays a critical role in the development and progression of DCM; therefore, different pathological mechanisms and their pharmacological strategies have been described. It can be illustrated as follows: (A) acceleration of cardiac dysfunction progression in type 1 diabetes mellitus (T1DM) with autophagy-related gene 5 (ATG5) KO, (B) the promotion of cardiac dysfunction by mammalian sterile 20-like kinase 1- (Mst1-) inhibited autophagic flow. Lin-28 homolog A (Lin28a) can inhibit Mst1 activating autophagy, (C) the inhibition of autophagic flow by the upregulation of miR-34a in the diabetic heart. As a pharmacological strategy, dihydromethicetin decreases the expression of miR-34a, restoring the impaired autophagy, (D) diabetic heart upregulates miR-207, which inhibits the autophagic flow in an LAPM2-dependent mechanism, and (E) miR-34a could inhibit the autophagic flux by targeting autophagy-related 9 A (ATG9A). Mitophagy, the mechanism by which damaged or defective mitochondria are eliminated, is strongly inhibited in DCM, being considered a pathological feature. For this reason, mechanisms and therapeutic strategies aiming at mitophagy recovery have also been included and represented as follows: (F) the inhibition of mitophagy by bromodomain-containing protein 4 (BRD4) that is restored by JQ1 in a PTEN-induced kinase 1- (PINK1-) dependent mechanism, (G) Mst1 decreases mitophagy using a PARKIN-dependent mechanism by inhibiting sirtuin 3 (SIRT3) expression; therefore, (H) SIRT3 KO reduces mitophagy also in a Parkin-dependent manner, and (I) Mst1 KO to induce mitophagy.