TABLE 6.

The effects of sacubitril/valsartan on myocardial mitochondrial function and apoptosis in animal studies.

Type of model	Treatment, dose and duration	Findings	References
5/6 nephrectomy rats-induced chronic kidney disease	Post-treatment 60 mg/kg for 8 weeks	↑ cardiac mitochondrial proteins (ATP synthase β, Porin 1)	Suematsu et al. (2018)
Chemogenetic rats model of persistent cardiac redox stress	Post-treatment 68 mg/kg orally for 4 weeks	↑ isocitrate dehydrogenase 2 expression	Sorrentino et al. (2019)
		↓ caspase 3
Doxorubicin-induced dilated cardiomyopathy in rats	Post-treatment 30 mg/kg/day/orally for 47 days	↓ cytosolic cytochrome C expression,	Yeh et al. (2021a)
		↓ cyclophilin-D expression
		↓ Drp1 expression
		↓ Mfn2 expression
		↓ electron transport chain complex subunits (I, II, III, and V) expression
		↓ mitochondrial Bax expression
		↓ cleaved caspase 3 expression
		↓ cleaved caspase 9 expression
		↓ percentage early and late apoptosis cells
H2O2-induced cell apoptosis in H9C2 cells	Pretreatment 12.5 μM	↑ mitochondrial-membrane potential,	Yeh et al. (2021b)
		↓ mitochondrial damage
		↓ p-Drp1 expression
		↓ Mfn2 expression
Cardiorenal syndrome rats fed with high-protein diet	Post-treatment 100 mg/kg/day, orally for 28 days	↑ mitochondrial cytochrome C expression	Yeh et al. (2021b)
		↓ cytosolic cytochrome C expression
		↓ cyclophilin-D expression
		↓ DRP1 expression
		↓ Mfn2 expression
		↓ PGC-1α expression
		↑ electron transport chain complex subunits (I,II, III, and V) expression
		↓ mitochondrial Bax protein expression
		↓ cleaved caspase 3 protein expression
		↓ cleaved Poly ADP-ribose polymerase
		↓ apoptosis signal-regulating kinase I
		↓ p-MMK4, ↓ p-MMK7, ↓ p-ERK, ↓ p-c-Jun
Simultaneous heart and kidney I/R-induced injury in rats	Post-treatment 10 mg/kg, orally at 30 min/followed by days 1–5 twice daily	↑ mitochondrial cytochrome C expression	Sung et al. (2022)
		↓ cytosolic cytochrome C expression
		↓ mitochondrial Bax expression
		↓ cleaved caspase 3 expression
		↓ cleaved Poly ADP-ribose polymerase expression
Doxorubicin-induced cardiotoxicity in mice	Concurrent treatment 80 mg/kg orally for 9 days	↓ caspase 3	Dindaş et al. (2021)
ox-LDL-induced inflammation and apoptosis in HUVECs	Pretreatment 10–4 μM	↓ apoptosis rate (%)	Bai et al. (2021)
		↓ cleaved caspase-3/caspase-3 expression
		↓ Bax expression
		↑ Bcl-2 expression
High-fat diet and streptozotocin induced-diabetic cardiomyopathy in rats	Post-treatment 68 mg/kg/day, gastric gavage for 8 weeks	↓ cleaved caspase-3 protein and mRNA expression	Belali et al. (2022)
		↓ Bax protein expression
		↑ Bcl-2 protein expression
		↓ Bax/Bcl-2 mRNA ratio
Doxorubicin-induced cardiotoxicity in rats	Concurrent treatment 60 mg/kg/day for 6 weeks	↓ apoptosis in the myocardium	Kim et al. (2022)
		↓ Bax protein expression
		↓ caspase 3 protein expression

ATP, adenosine triphosphate; Bcl-2/Bax; B cell lymphoma 2/Bcl-2-associated X ratio; Drp1, dynamin‐related protein one; HUVECs, human umbilical vein endothelial cells; I/R, ischemia reperfusion; p-ERK, phosphorylated extracellular signal-regulated kinase; p-c-Jun, phosphorylated c-Jun; PGC-1α, peroxisome proliferator-activated receptor coactivator-1α; mfn2, mitofusin two; p-MMK4, phosphorylated mitogen-activated protein kinase kinase four; MMK7, phosphorylated mitogen-activated protein kinase kinase seven; ox-LDL, oxidized low-density lipoprotein; ↓, decrease; ↑, increase.