TABLE 1.

Mechanisms of flavonoids included in cardiovascular diseases.

Author (year)	Study design	Flavonoid	Dose	Duration	Cardiovascular disease	Outcomes	Chemical structure
Cai et al. (2015)	In vitro	Quercetin	0–20 μM	24 h	Atherosclerosis	• Prevents apoptosis
						• Prevents lipid accumulation in RAW264.7 macrophages
Chang et al. (2021)	In vitro	Quercetin	50, 100, 150, 200, and 250 mg/L	Every 2 days	Cardiomyocyte apoptosis	• Regulates mitophagy
						• Regulates ER stress
Zhang et al. (2017b)	In vivo	Nobiletin	50 mg/kg	4 weeks	Cardiac hypertrophy	• Inhibits oxidative stress
						• Inhibits ER stress
						• Regulates ER stress
Arumugam et al. (2012)	In vivo	Quercetin	10 mg/kg/day	28 days	Experimental autoimmune myocarditis	• Suppression of both the mitogen-active protein kinases (MAPK) and the myocardial endothelin-1
						• Suppression of oxidative and ER stress
						• Cardioprotection against experimental autoimmune myocarditis
Jasuja et al. (2012)	In vivo	Quercetin-3-O-rutinoside	0–50 mg/kg	90 min	Thrombosis	• Inhibition of thrombus formation and fibrin generation and platelet aggregation
			0–100 μM			• Selective inhibition of PDI
Zhang et al. (2013a)	in vivo and in vitro	Ghrelin	10–8 mol/kg/day	4 days	Apoptosis	• Inhibition of myocardial ER stress and
			Every 12 h			• Protection of the heart against ER stress-induced apoptosis by activating AMP-activated protein kinase
Tang et al. (2017)	In vitro	Naringenin	0–160 μM	24 h	Hypoxia/reoxygenation-induced apoptosis and cytotoxicity	• Amelioration of hypoxia/reoxygenation-induced endoplasmic reticulum stress-mediated apoptosis in H9c2 myocardial cells
Qian et al. (2021)	In vivo	Icariin	10–40 mg/kg per day	2 weeks	Cardiomyocyte apoptosis	• Enhancement of left ventricular function and an increase in stroke output and ejection fraction
						• Prevention of ER stress-induced apoptosis
Zhang et al. (2013b)	In vitro	Icariin	0–20 μM	30 min	Cardiac H9c2 cells apoptosis	• Protection of Rat Cardiac H9c2 Cells from Apoptosis
						• Inhibiting Endoplasmic Reticulum Stress
Shen et al. (2014)	In vitro	Baicalin	0–50 µM	24 h	ER stress-induced apoptosis of cardiomyocytes	• Protection of cardiomyocytes from ER stress-induced apoptosis via CHOP/eNOS/NO pathway
Yu et al. (2019a)	In vitro and in vivo	Naringenin	50 mg/kg/d	5 days	H9c2 cardiomyoblasts and MI/R-injured rat heart	• Increased myocardial cGMP
						• Upregulated PKGIα expression
						• Higher antioxidant enzyme expression
						• Decreased myocardial oxidative stress levels
Kim et al. (2008)	In vitro and in vivo	Kaempferol	10 µM	20 min	MI/R-injured H9c2 cardiac muscle cells	• Increase in Bcl-2 (anti-apoptotic protein) expression
						• Decrease in Bax (apoptotic protein) expression
						• Down-regulation of proteins involved in ER stress
						• Improved the post-ischemic left ventricular end-diastolic pressure and also left ventricular diastolic pressure
Zhang et al. (2019b)	In vivo	Nobiletin	15, 30, and 45 mg/kg	Pre-treatment	MI/R-injured rat heart	• Downregulated mRNA and protein levels of ER stress-related signal molecules including GRP78, caspase-12, and CHOP
						• Increased levels of p-PI3K and p-AKT
						• Mediated ER stress by PI3K/AKT pathway
Feng et al. (2018)	In vitro	Apigenin	NR	Pre-treatment	MI/R-injured rat cardiomyocytes	• Enhanced cardiac performance
						• Reduced ER stress by stimulating the AMPK signaling pathway
						• Reduced cell apoptosis
						• Improved cell viability
Shu et al. (2019)	In vitro	Dihydroquercetin	5, 10, 20 µM	20 min	MI/R-injured rat cardiomyocytes	• Inhibited the apoptotic pathways by decreasing CHOP and p-JNK
						• Postpone the onset of ER stress by decreasing (P-EIF2), PERK and GRP78
						• Stimulated the expression of HO-1
						• Increased Nrf2 binding to antioxidant response elements
Kim et al. (2010)	In vitro	Flavonoids	10 µM biochanin A, 1 µM daidzein, 25 µM genistein, 10 µM luteolin, 50 µM quercetin or 50 µM rutin	30 min	MI/R-injured rat cardiomyocytes	• Raised the expression of Bcl-2	Many flavonoids
						• Reduced the Bax
						• Decreased the glucose-regulated protein-78, inositol-needing protein-1, X-box binding protein 1, C/EBP-homologous protein, and phosphor-eukaryotic initiation factor 2α
Zhu et al. (2017b)	In vitro	Luteolin	8 µM	12 h	MI/R-injured rat cardiomyocytes	• Increased SERCA2a activity
						• Decreased the inhibitive results of the p38 pathway
Badawy Khair and Mohammed, (2021)	In vivo	Silymarin	NR	3 months	Atherosclerosis	• Reduced loss and disruption of Purkinje cell layer with pyknotic nuclei
						• Reduced dilated cisternae of rough ER
						• Prevented increase in GFAP, Cox-2 immunoreactivity
Liew et al. (2003)	In vitro	Genistein	40 µM	5 min	Cardiomyocyte contraction	• Stimulated myocyte contraction
						• Inhibited the primary stimulus of cell contraction namely the L-type Ca2+ current
						• Enhanced the SR Ca2+ load
						• Transient increase in Ca2+ through Na+/Ca2+ exchanger dysfunction
						• Influenced the phosphorylation of phospholamban
						• Speeded up SR release by affecting the ryanodine receptor
Feng et al. (2012)	In vitro	EGCG	1–100 µM	5 min	Cardiomyocyte contraction	• Increased the contractility of unchanged murine myocytes
						• Raised SR Ca2+ content
						• Electrically stimulated Ca2+ transients
						• Inhibited the Na+/Ca2+ exchanger
						• Ca2+-ATPase, Na + -K + ATPase, and Na + -H+ exchanger, were not affected
Hamaguchi et al. (2021)	In vivo	Quercetin	10–30 µM	4–6 weeks	Diastolic dysfunction	• Accelerating myocardial relaxation through ER Ca2+-ATPase activation
Zhou et al. (2016)	In vivo and in vitro	Flavonoids of Astragalus (TFA)	5–50 mg/kg	7 days	Viral myocarditis	• Preventing down regulation of ER chaperone calumenin expression and rescuing calumenin interaction and SERCA2
Kim et al. (2008)	In vitro	Kaempferol	10 μM	19:50′	Ischemic/Reperfusion induced Cardiac Dmage	• Decreased apoptosis of heart muscle cells by increasing the anti-apoptotic protein BCL2 and also decreasing the expression of ER stress proteins
Qu et al. (2015)	In vivo	Wogonin	.1–100 µM	3:50′	Hypertension	• inhibition of both intracellular Ca2+ release and extracellular Ca2+ influx
Xu et al. (2019)	In vivo and in vitro	Naringenin	100 mg/kg/d	12 weeks	Atherosclerosis	• Cholesterol efflux regulator through the ATF6 branch of ER stress and PI3K/AKT pathway
Dai et al. (2017)	In vivo	Baicalin	2 ml of 100 mg/kg daily	4 weeks	Myocardial fibrosis	• Reduction of ER stress and myocardial apoptosis and reverting left ventricular remodeling
Ge et al. (2019)	In vivo and in vitro	Fisetin	40 mg/kg daily	16 weeks	Cardiac dysfunction	• Prevention of myocardial inflammation and fat deposition and cardiomyopathy by inhibiting ER signaling
Wu et al. (2019)	In vivo	Icariside II	4–16 mg/kg daily	13 weeks	Hypertensive heart disease	• Prevention of ER-induced hypertensive disease by reducing cardiomyocyte apoptosis through inhibition of the PERK/ATF-4/CHOP signaling pathway
Ashokkumar et al. (2018)	In vivo	Vitexin	1.5 mg/kg.b.wt	30 days	Myocardial injury	• Enhanced cardioprotective effects by coordinated activation of ER stress