The potential of herbal drugs to treat heart failure: The roles of Sirt1/AMPK

Abstract

Heart failure (HF) is a highly morbid syndrome that seriously affects the physical and mental health of patients and generates an enormous socio-economic burden. In addition to cardiac myocyte oxidative stress and apoptosis, which are considered mechanisms for the development of HF, alterations in cardiac energy metabolism and pathological autophagy also contribute to cardiac abnormalities and ultimately HF. Silent information regulator 1 (Sirt1) and adenosine monophosphate-activated protein kinase (AMPK) are nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylases and phosphorylated kinases, respectively. They play similar roles in regulating some pathological processes of the heart through regulating targets such as peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), protein 38 mitogen-activated protein kinase (p38 MAPK), peroxisome proliferator-activated receptors (PPARs), and mammalian target of rapamycin (mTOR). We summarized the synergistic effects of Sirt1 and AMPK in the heart, and listed the traditional Chinese medicine (TCM) that exhibit cardioprotective properties by modulating the Sirt1/AMPK pathway, to provide a basis for the development of Sirt1/AMPK activators or inhibitors for the treatment of HF and other cardiovascular diseases (CVDs).

Keywords: Adenosine monophosphate-activated protein kinase; Heart failure; Silent information regulator 1; Traditional Chinese medicine.

Graphical abstract

Fig. 1

The interaction between silent information regulator 1 (Sirt1) and adenosine monophosphate-activated protein kinase (AMPK) and the downstream targets regulated by them together. In the presence of AMPK or Sirt1 activators, AMPK can promote the nicotinamide adenine dinucleotide (NAD⁺)/NADH ratio to activate Sirt1 or GAPDH phosphorylation to enhance Sirt1 expression, and Sirt1 can activate AMPK by deacetylating liver kinase 1 (LKB1), among other ways. AMPK and Sirt1 can also interact in cardiomyocytes. Additionally, through controlling several common targets (such as peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), peroxisome proliferator-activated receptor α (PPARα)), AMPK and Sirt1 may regulate the metabolism of cardiac fatty acids, glucose, and other substrates, improving autophagy (by mechanistic target of rapamycin (mTOR)), reducing oxidative stress (by nuclear factor erythroid2-related factor 2 (Nrf2) and forkhead box family and subfamily O of transcription factors (FOXOs), and reducing apoptosis (by p53 and mitogen-activated protein kinase (MAPK) family). Where represents indicates stimulation/promoting, indicates reduction/inhibition. ROS: reactive oxygen species; SOD: manganese-superoxide dismutase; GLUT4: glucose transporter type 4; eNOS: endothelial nitric oxide synthase; FOXO4: forkhead box family and subfamily O of transcription factors 4; FOXO3: forkhead box family and subfamily O of transcription factors 3; NQO1: NAD(P)H-quinone oxidoreductase 1; HO-1: heme oxygenase-1; SAPK: stress-activated protein kinase; TNF-α: tumor necrosis factor α; BAD: Bcl-2 associated agonist of cell death; Bax: Bcl2-associated x; JNK: c-Jun NH2-terminal kinase; NF-κB: nuclear factor-kappa-B; p38 MAPK: protein 38 mitogen-activated protein kinase; ERK1/2: extracellular signal-regulated kinase; Nampt: nicotinamide phosphoribosyl transferase; eEF2K: elongation factor-2 kinase; eIF2α: eukaryotic initiation factor-2α; mTORC1: mammalian target of rapamycin compound 1; mTORC2: mammalian target of rapamycin compound 2; Akt: protein kinase B; PINK: PTEN-induced kinase 1; ULK1: unc-51-like kinase 1; Atg5: autophagy-related genes 5; Atg7: autophagy-related genes 7; Atg8: autophagy-related genes 8; PFK-2: phosphofructokinase-2; AICAR: aminoimidazole carboxamide ribotide; ATP: adenosine triphosphate; AMP: adenosine monophosphate.

Fig. 2

The protective effects of traditional Chinese medicine extract on heart through silent information regulator 1 (Sirt1)/adenosine monophosphate activated protein kinase (AMPK) pathway. Some common herbal drugs extracts active ingredients work to improve heart autophagy, lower cardiomyocytes apoptosis, and reduce oxidative stress by regulating the Sirt1/AMPK signal pathways. As a result, cardiac function is improved, the size of heart infract is reduced, and therefore progression of heart failure (HF) is slowed. The above herbal pictures are reprinted from GBIF.org (year) citation guidelines. Available from https://www.gbif.org/citation-guidelines with permission and was partly generated using Servier Medical Art, provided by Servier, licensed under a creative commons attribution 3.0 unported license.

Fig. 3

The possible molecular mechanisms for constituents from herbal medicines to treat HF via activation of AMPK/Sirt1 signaling. Some monomer compounds of traditional Chinese medicine, such as resveratrol, up-regulate the expression of the GLUT4 protein to promote glucose transport, promote the expression of Bcl-2 to inhibit apoptosis, and up-regulate the expression of the Nrf2 protein to reduce the level of oxidative stress in the heart by activating Sirt1 and AMPK. In addition, these compounds also regulate the tricarboxylic acid cycle through the Sirt1/AMPK pathway to combat the imbalance of myocardial energy metabolism, regulate the opening of mPTP channels to maintain mitochondrial function, regulate autophagy, and inhibit endoplasmic reticulum oxidative stress to maintain normal cell physiological function. Where represents indicates stimulation/promoting, indicates reduction/inhibition. LAD: ligation of the left anterior descending coronary artery; MI/RI: myocardial ischemia-reperfusion injury; ISO: isoprenaline; HF: heart failure; Ang II: angiotensin II; GLUT4: glucose transporter type 4; PGC-1α: peroxisome proliferator-activated receptor γ coactivator 1α; AMPK: adenosine monophosphate activated protein kinase; LC-3: light chain 3; TNF-α: tumor necrosis factor α; HO-1: heme oxygenase-1; Nrf2: nuclear factor erythroid2-related factor 2; NQO1: NAD(P)H-quinone oxidoreductase 1; PDH: pyruvate dehydrogenase; MPC Ⅰ/Ⅱ: mitochondrial pyruvate carrier Ⅰ/Ⅱ; p62: sequestosome 1; mTOR: mammalian target of rapamycin; Akt: protein kinase B; Sirt1: silent information regulator 1; NLRP3: NOD-like receptor protein 3; NF-κB: nuclear factor-kappa-B; PPARα: peroxisome proliferator-activated receptor α; JNK: c-Jun NH2-terminal kinase; Bcl-2: B-cell lymphoma-2; PINK: PTEN-induced kinase 1; TMBIM6: transmembrane BAX inhibitor motif containing 6; CHOP: C/EBP-homologous protein; PERK: protein kinase R (PKR)-like endoplasmic reticulum kinase; TFAM: mitochondrial transcription factor A; FOXOs: forkhead box family and subfamily O of transcription factors; TCA: tricarboxylic acid; mPTP: mitochondrial permeability transition pore; Bcl-2: B-cell lymphoma-2; Bax: Bcl-2-associated x. The above herbal pictures are reprinted from Reprinted from GBIF.org (year) citation guidelines. Available from https://www.gbif.org/citation-guidelines with permission and was partly generated using Servier Medical Art, provided by Servier, licensed under a creative commons attribution 3.0 unported license.