Table 1.
The table shows the different macroautophagy-related proteins found in mammals and yeast. It also summarizes the different gain- and loss-of function models of macroautophagy which have been utilized for studying the role of macroautophagy in cardiac pathology. In this review, the nomenclature of autophagy-related genes and proteins have been adopted following “Guidelines for the Use and Interpretation of Assays for Monitoring Autophagy (3rd Edition)” [135]. ∗∗ indicates that the loss or gain of an ATG gene has not been studied in the heart. GABARAP: gamma-aminobutyrate receptor-associated protein; GABARAP: GABA type A receptor-associated protein; GABARAPL1: GABA type A receptor-associated protein like 1; GABARAPL2: GABA type A receptor-associated protein like 2; GATE-16: Golgi-associated ATPase enhancer of 16 kDa; SNX30: sorting nexin family member 30; SNX4: sorting nexin family member 4; ULK 1: unc-51-like autophagy activating kinase 1; ULK 2: unc-51-like autophagy activating kinase 2; WIPI1: WD repeat domain, phosphoinositide interacting 1; WIPI2: WD repeat domain, phosphoinositide interacting 2; WIPI3: WD repeat domain, phosphoinositide interacting 3; WIPI4: WD repeat domain, phosphoinositide interacting 4.
| Mammals | Yeast | Mammalian genetic models of autophagy | Results |
|---|---|---|---|
| ULK 1 | Atg1 | Loss of function: Cardiac-specific Ulk1 deletion: Myh6-cre/ulk1flox/flox Lipoprotein lipase deletion: Myh6-cre/Lplflox/flox Combined deletion: Myh6-cre/ulk1flox/flox, Lplflox/flox |
Potential therapeutic strategy for regulating cardiac lipoprotein lipase activity in obesity-related cardiomyopathy [73] |
| ULK 2 | |||
|
| |||
| ATG2A ATG2B |
Atg2 | ∗∗ | Role in cardiac pathology is not known. |
|
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| ATG3 | Atg3 | ∗∗ | Role in cardiac pathology is not known. |
|
| |||
| ATG4A ATG4B ATG4C ATG4D |
Atg4 | Loss of function: knockout of rat Atg4B and human ATG4B to define the mechanism of action and tissue distribution of ATG4B | ATG4B is expressed lowly in rat hearts [221]. Its function in cardiac pathology is not known. |
|
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| ATG5 | — | Loss of function: tamoxifen inducible Atg5 in atg5flox/flox: MerCreMer+ (atg5flox/flox; Cre+); and atg5flox/flox: MerCreMer− (atg5flox/flox) mice | During heart failure, increase in autophagy is a protective mechanism adapted by the heart [65]. |
| A dominant form of atg5, atg5K130R, was expressed in mouse HL-1 cells. | Autophagy plays a protective role during I/R injury in cardiomyocytes [66]. | ||
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| |||
| ATG6/BECN1 | Atg 6/Vps30 | Loss of function: Beclin 1+/− transgenic mice Gain of function: Beclin 1 overexpression driven by the cardiomyocyte-specific α-MHC promoter |
Autophagy contributes to the pathogenesis of pressure overload-induced heart failure [71]. |
| Loss of function: heterozygous deletion of Beclin 1 (BCN1+/−) Gain of function: BCN1 single transgenic mice and tetracycline-controlled BCN1-tTA double transgenic (DTG) mice |
Loss of autophagy protective in diabetic induced cardiac injury [70] | ||
| Loss of function: GFP-LC3/Beclin 1+/− transgenic mice | Beclin 1 deletion leads to loss of autophagy and is protective in I/R injury [72]. | ||
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| ATG7 | Atg7 | Gain and loss of function: CryABR120G expressing cardiomyocytes were treated with Atg7 siRNA and Atg7 adenovirus. Gain of function: doxycycline-controlled expression of Atg7 in transgenic mice |
ATG7 plays an important role in ameliorating the pathology associated with CryABR120G [2, 67]. |
| Loss of function: tamoxifen-inducible cardiac-specific Atg7flox/flox; Cre | Autophagy is protective during myocardial ischemic reperfusion [69]. | ||
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| GABARAP subfamily [222] GABARAP/ATG8A GABARAPL1/GEC1/ATG8B GABARAPL2/GATE16/ATG8C |
Atg8 | ∗∗ | Role in cardiac pathology is not known. |
| LC3 subfamily [222] MAPLC3A, MAPLC3B, MAPLC3BII, MAPLC3C |
LC3-II levels are used as indicators for studying autophagy [124–127]. | ||
|
| |||
| ATG9A ATG9B |
Atg9 | ∗∗ | Role in cardiac pathology is not known. |
| ATG10 | Atg10 | ∗∗ | Role in cardiac pathology is not known. |
| Not identified | Atg11 | ∗∗ | |
| ATG12 | Atg12 | ∗∗ | Role in cardiac pathology is not known. |
|
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| ATG13 | Atg13 | Loss of function: atg13-deficient mice were generated using CRISPR/Cas9 system. | Loss of Atg13 causes myocardial growth defects in developing embryos [75]. |
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| ATG14/ATG14L/BAKOR | Atg14 | ∗∗ | Role in cardiac pathology is not known. |
| Not identified | Atg15 | ∗∗ | |
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| ATG16L1 ATG16L2 |
Atg16 | A gene trap-induced hypomorphic allele of the Atg16L1 (atg16L1-HM) | Loss of autophagy is protective in diabetic-induced cardiac injury [70]. |
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| RB1CC1 (RB1-induced coiled coil 1)/FIP200 | Atg17 | Loss of function: FIP200Δ/Δ mice caused by FIP200 gene ablation and FIP200flox/flox were generated. | FIP200 is important for normal cardiac development, and its deletion causes embryonic lethality involving defects in the heart and liver [74]. |
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| WIPI1, WIPI2, WIPI3, WIPI4 | Atg8 | ∗∗ | Role in cardiac pathology is not known. |
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| Not identified | Atg19, Atg20 | ___ | ___ |
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| WIPI2 (WD repeat domain, phosphoinositide interacting 2) | Atg21 | ∗∗ | Role in cardiac pathology is not known. |
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| Not identified | Atg22, Atg23 | ___ | ___ |
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| SNX30 | Atg24A | ∗∗ | Role in cardiac pathology is not known. |
| SNX4 | Atg24B | ||
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| Not identified | Atg25, Atg26 Atg27, Atg28 Atg29, Atg30 Atg31 |
___ | ___ |
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| BCL2L13 (BCL2-like 13)/Bcl2-RAMBO | Atg32 | Loss of function: Bcl2-L-13 siRNA Gain of function: overexpression of Bcl2-L-13 |
The role of BCL2L13 in mitochondrial homeostasis was studied [220]. Role in cardiac pathology is not known. |
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| Not identified | Atg33, Atg34 Atg35 |
___ | ___ |
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| ATG101 | Atg101 | ∗∗ | Role in cardiac pathology is not known. |