An Intervention Target for Myocardial Fibrosis: Autophagy

Table 1

Potential effect of autophagy in the treatment of myocardial fibrosis.

Medicine	Disease	Cells/tissues	Effects	Mechanisms	Pathway	Reference
Atorvastatin	AMI	Rat	Autophagy ↑	Ejection fraction, LC3 ↑; Fibrosis, infarcted area, inflammatory level, Bax ↓	AMPK/mTOR pathway	[22]
Atorvastatin	Hypertension-induced cardiac hypertrophy	SHRs	Autophagy ↑	Expression of protein-1 light chain 3-II and Beclin-1 protein ↑; Akt and mTOR expression ↑	Akt/mTOR pathway	[23]
Cucurbitacin B	Pressure overload- induced cardiac hypertrophy	AB-induced mice	Autophagy ↑	Heart weight, cross-sectional area Interstitial fibrosis ↓; Systolic and diastolic ↑; Normalized in gene expression; Reserved microvascular density	Akt/mTOR/FoxO3a signal axis	[24]
Trimetazidine	Diabetic cardiomyopathy	Type 2 DCM rat	Autophagy ↑	CVF, PVCA/LA ratio, phosphorylation of ERK and P38 MAPK ↓; Phosphorylation of AMPK, the interaction between Bcl-2 and Beclin-1 ↑	PI3K/AKT and AMPK pathways	[25]
Liraglutide	Diabetic cardiomyopathy	ZDF rat	Autophagy ↑	CK, LDH, mTOR phosphorylation ↓; AMPK phosphorylation ↑	AMPK-mTOR signaling pathway	[26]
1,25-Dihydroxyvitamin-D3	Diabetic cardiomyopathy	STZ-induced type 1 diabetic rat; High-glucose cultured H9C2 cells	Autophagy ↑	Myocardial hypertrophy and interstitial fibrosis ↓; Cardiac function ↑	β-Catenin/TCF4/GSK-3β and mTOR pathway	[27]
Spermidine	Physiological cardiac aging	Wild-type C57BL/6 mice	Autophagy ↑	LC3-II, autophagic flux ↑; Cardiac hypertrophy ↓; Preserved diastolic function		[28]
Isoflurane	Cardiomyocytes from A/R injury	Cardiomyocytes from rat	Autophagy ↓	Cell viability ↑; Autophagosome generation, expression of NOD2 ↓	P38MAPK pathway	[29]
Aliskiren	Pressure overload-induced heart hypertrophy and fibrosis	TAC mice	Autophagy ↓	Expression of Atg5 and Atg16 L1 mRNAs, LC3-II and Beclin-1 proteins ↓	Ang II-PKCβI-ERK1/2-regulated autophagy	[30]
Calhex 231	Cardiac hypertrophy	TAC or Ang II-induced rat	Autophagy ↓	CaSR expression, autophagy levels ↓	CaMKKβ-AMPK-mTOR pathway	[31]
Hydrogen sulfide	Diabetic myocardial	STZ-induced diabetic rat	Autophagy ↓	Myocardial fibrosis, myocardial autophagy ↓; PI3K/AKT1 pathway ↑	PI3K/AKT1 signaling pathway	[32]
Chloroquine	Diabetic cardiomyopathy.	STZ-induced diabetic mice	Autophagy ↓	Ameliorated cardiac diastolic function; autophagolysosomes, cardiomyocyte apoptosis, cardiac fibrosis ↓; LC3-II, p62 expression ↑	mTOR pathway	[33]
Multi-Strain Probiotics	Obesity-induced cardiac fibrosis	HF diet-induced obese rat	Autophagy ↓	TGF/MMP2/MMP9 fibrosis pathways, ERK5/uPA/ANP cardiac hypertrophy pathways ↓; Beclin-1/LC3B/Atg7 pathway ↑	TGF/MMP2/MMP9 fibrosis pathways,; ERK5/uPA/ANP cardiac hypertrophy pathways,; Beclin-1/LC3B/Atg7 autophagy pathway	[34]
Phellinus linteus Mycelium	Myocardial I/R Injury	I/R rat	Autophagy balance	Infarct size, plasma lactate dehydrogenase level, caspase-3, caspase-9, Beclin-1, p62, mTOR level ↓; Bcl-2/Bax ratio, AMPK Phosphorylation ↑	AMPK-dependent pathway,; Beclin-1-dependent pathway	[35]

Note. AMI, acute myocardial infarction; AMPK, AMP-activated protein kinase; mTOR, mammalian target of rapamycin; SHRs, spontaneously hypertensive rats; AB, aortic banding; CVF, collagen volume fraction; ERK, extracellular regulated protein kinases; MAPK, mitogen-activated protein kinases; DCM, diabetic cardiomyopathy; ZDF, Zucker diabetic fatty; CK, creatine kinase; LDH, lactate dehydrogenase; STZ, streptozotocin; A/R, anoxia/reoxygenation; NOD2, nucleotide binding oligomerization domain containing 2; TAC, transverse aortic constriction; Atg, autophagy-related gene; ATG16 L1, autophagy-related 16-like 1; LC3-II, Light chain 3-II; P38 MAPK, P38 mitogen-activated protein kinase; ERK, extracellular signal regulated kinase; PKC, protein kinase C; Ang II, angiotensin II; CaMKK β, Ca 2+/calmodulin-dependent-protein kinase-kinase-β; CaSR, calcium-sensing receptor; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; HF, high-fat; TGF, transforming growth factor; MMP2, matrix metalloproteinase-2; MMP9, matrix metalloproteinase-9; I/R, ischemia-reperfusion.