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.