SHANK3 Co-ordinately Regulates Autophagy and Apoptosis in Myocardial Infarction

Abstract

Cardiac remodeling and dysfunction are responsible for the high mortality after myocardial infarction (MI). We assessed the potential for Shank3 to alleviate the post-infarction cardiac dysfunction. The experimental MI mice model was constructed by left anterior descending coronary artery ligation. Shank3 knockout aggravated cardiac dysfunction after MI, while Shank3 overexpression alleviated it. The histological examination showed that the infarct size was significantly increased in the acute phase of MI in the Shank3 knockout group, and the cardiac dysfunction of the Shank3 knockout group was even more severe than the Shank3 overexpression group, revealed by echocardiography analyses. In vitro, cultured neonatal cardiomyocytes were subjected to simulated MI. Shank3 downregulation curbed LC3 expression and autophagosome-lysosome fusion. Furthermore, Shank3 downregulation increased cardiomyocyte apoptosis. In contrast, Shank3 upregulation induced autophagy, and inhibited apoptosis under hypoxia. In vivo, western blot analysis showed decreased levels of Atg7, Beclin1, LC3-II, and Bcl-2 as well as increased expression of p62, cleaved caspase-3, and cleaved caspase-9 in the Shank3 knockout group which suffered from MI. On the other hand, it also revealed that Shank3 overexpression induced autophagy and inhibited apoptosis after MI. Shank3 may serve as a new target for improving cardiac function after MI by inducing autophagy while inhibiting apoptosis.

Genetic mouse models of autism spectrum disorder present subtle heterogenous cardiac abnormalities

“…In the Arid1b (+/À) group, we observed arterial stenosis at the level of the aortic valve, in agreement with clinical reports (de Rubeis & Buxbaum, 2015;Pierpont et al, 2018). In the Shank3 (exon 4-9) group we observed myocardial changes (increased anterior and posterior was thickness) which is consistent with the reported role of Shank3 in myocardial remodeling (in mice; Cusmano-ozog et al, 2007;Lim et al, 1999;Man et al, 2020). Our findings could also be a downstream effect of patent ductus arteriosus (PDA), septal defects or right heart dysfunction, all of which have been reported (Phelan & McDermid, 2012;Pierpont et al, 2018).…”

“…Congenital heart disease has been reported in 33% of patients, specifically, Tetralogy of Fallot (ToF), bicuspid aortic valve and pulmonary atresia (Pierpont et al, 2018). In the case of Shank3 ( Δexon 4–9 ), abundant Shank3 mRNA has been detected in the heart, while mouse studies have demonstrated the involvement of Shank3 in myocardial remodeling following myocardial infarction (Cusmano‐ozog et al, 2007; Lim et al, 1999; Man et al, 2020). Even more, in Phelan‐McDermid syndrome (Shank3 microdeletion), a series of cardiac abnormalities have been reported in patients, with a prevalence of congenital heart disease >25% (patent ductus arteriosus, ventricular and atrial septal defects, total anomalous pulmonary venous return; Phelan & McDermid, 2012; Pierpont et al, 2018).…”

Investigation of candidate genes and mechanisms underlying obesity associated type 2 diabetes mellitus using bioinformatics analysis and screening of small drug molecules

“…The GO and pathway enrichment analysis of DEG are closely related to obesity associated type 2 diabetes mellitus. Genes such as KCNE5 [ 45 ], SHANK3 [ 46 ], CASQ2 [ 47 ], EDNRA (endothelin receptor type A) [ 48 ], EPHB4 [ 49 ], ALPK3 [ 50 ], WNT11 [ 51 ], IRAK2 [ 52 ], FBN1 [ 53 ], SFRP2 [ 54 ], CLCA2 [ 55 ], NEXN (nexilin F-actin binding protein) [ 56 ], PALLD (palladin, cytoskeletal associated protein) [ 57 ], DAB2 [ 58 ], NRP2 [ 59 ], THBS2 [ 60 ], CSF1R [ 61 ], KCNA2 [ 62 ], CACNA1C [ 63 ], F2R [ 64 ], UCHL1 [ 65 ], CCL18 [ 66 ], ITGB1BP2 [ 67 ] and FMOD (fibromodulin) [ 68 ] were reportedly involved in cardio vascular diseases, but these genes might be key for progression of obesity associated type 2 diabetes mellitus. Hu et al [ 69 ], Liu et al [ 70 ], Eltokhi et al [ 71 ], Cai et al [ 72 ], Pfeiffer et al [ 73 ], Lin et al [ 74 ], Royer-Zemmour et al [ 75 ], Pastor et al [ 76 ], Goodspeed et al [ 77 ], Zhang et al [ 78 ], Rogers et al [ 79 ], Su et al [ 80 ] and Foale et al [ 81 ] reported that NRXN1, CRHR1, SHANK2, PSEN2, CKB (creatine kinase B), CD200R1, SRPX2, PTPRZ1, SLC6A1, GABRB2, KCNA1, ASAH1 and LINGO1 were the genes expressed in progression of neuropsychiatric disorders, but these genes might be involved in advancement of obesity associated type 2 diabetes mellitus.…”

Cortactin Modulates Lung Endothelial Apoptosis Induced by Cigarette Smoke

“…Several CTTN SH3 binding partners are associated with the regulation of the apoptotic pathway and could participate in mediating this effect. These include SHANK2, Arp2/3, and Dynamin 2 [ 51 , 52 , 53 ]. Another important cytoskeletal binding partner for CTTN at its SH3 domain is nmMLCK [ 23 , 35 ].…”