Table 1.

Cardioprotective effect and mechanism of action of resveratrol in preclinical studies.

Target HDAC or HAT	Molecular pathway	Experimental model	Cardiovascular effect	Reference
↑ Sirt1	↑ PGC-1α ↑ Bcl2 ↓ Bax, caspase 3 ↑ SOD, SDH, Cyt-c oxidase	TAC induced myocardial infraction In vivo Hypoxia induced dysfunction In vitro	↑ LVEF ↓ fibrosis ↓ apoptosis	[52]
↑ Sirt3	↓ TGF-β/Smad3	TAC induced heart failure In vivo	↓ fibrosis ↓ collagen deposition ↓ cardiac hypertrophy Prevented decrease in cardiac FS Preserved diastolic function	[53]
↑ Sirt1	↑ SOD	Chronic heart failure model In vivo Ang II or antimycin A induced oxidative stress In vitro	↑ FS ↑ LVEF ↑ survival ↓ apoptosis	[54]
↑ Sirt3	↑ SOD	Dox-induced mitochondrial dysfunction In vivo In vitro	↓ oxidative stress ↑ ATP mitochondrial production	[32]
↑ Sirt1	↓ p38MAPK ↓ caspase 3 ↓ Bax ↑ Bcl-2 ↑ SOD1	Dox-induced heart failure In vivo	↑ FS ↓ apoptosis ↓ oxidative stress	[55]
↑ Sirt1	↑ AMPK	Dox-induced cardiotoxicity In vitro	↑ survival	[56]
↑ Sirt3	↓ p53 ↓ Bax, Cyt-c	Dox-induced cardiotoxicity In vivo	↓ apoptosis Attenuated loss of diastolic and systolic function.	[57]
↑ Sirt1	↓ USP7 ↓ p300 ↓ Bax, caspase 3 ↓ p53	Dox-induced cardiotoxicity in young and aged hearts In vivo	↑ FS ↑ EF ↓ LVEDS ↓ apoptosis	[58]
↑ Sirt1	↑ PI3K-Akt ↓ TNF-α ↓ FAS/FADD/caspase 8 ↓ caspase 3 ↑ FoxO3	Exercise during aging In vivo	↑ FS ↓ fibrosis ↓ apoptosis	[41]
↑ Sirt1	↓ ac-FoxO1 ↓ Bim, Bax ↓ p53	Aging In vivo	↑ FS ↑ LVEF ↓ fibrosis ↓ apoptosis	[40]
↑ Sirt1	↑ SOD ↑ GSH	High glucose-induced mitochondrial oxidative stress. In vitro	↓ oxidative stress	[59]
↑ Sirt1	↓ p53 ↑ SDF-1	NE-induced hypertrophy In vitro Hypertension model In vivo	↓ hypertrophy ↑ bioavailable NO ↓ apoptosis	[60]
In T1DM: ↑ Sirt1, Sirt2, Sirt3, and Sirt5. In T2DM: ↑ Sirt1 and Sirt2 ↓ Sirt3, which was initially elevated	↓ B-MHC ↓ Akt	T1DM-induced cardiomyopathy In vivo T2DM-induced cardiomyopathy In vivo	In T1DM rats: ↓ cardiac atrophy In T2DM rats: ↓ cardiac hypertrophy	[61]
↑ Sirt1, Sirt3, Sirt4, and Sirt7	↓ caspase 3	H2O2-induced apoptosis In vitro	↓ apoptosis	[62]
Most effects abolished when using sirtinol	↑ SOD1, SOD3, GPx1, catalase. ↓ NOX2, NOX4 ↑ GTP cyclohidrolase 1 and biopterin	In vivo Apo-lipoprotein E Knockout mice	↓Oxidative stress Reversed eNOS uncoupling	[63]

AMPK: adenosine monophosphate-activated kinase; Ang II: angiotensin II; B-MHC: myosin heavy chain B; Cyt-c: cytochrome c; Dox: doxorubicin; FS: fractional shortening; Gpx1: glutathione peroxidase 1; GSH: glutathione; LVEF: left ventricular ejection fraction; NE: norepinephrine; NOX: NAD(P)H oxidase; PGC1-α: peroxisome proliferator activator of transcription (PPARy) co-activator 1α; TAC: transverse aortic constriction; T1DM: type 1 diabetes mellitus; T2DM: type 2 diabetes mellitus; SDF-1: stroma cell derived factor 1; SHD: succinate dehydrogenase; SOD: superoxide dismutase. USP7: ubiquitin-specific-processing protease 7.