Role of sirtuin 1 in depression‑induced coronary heart disease: Molecular pathways and therapeutic potential (Review)

Figure 1. Schematic figure, illustrating how SIRT1 regulates apoptosis, oxidative stress, autophagy and inflammation via its deacetylation activity. SIRT1 primarily exerts its regulatory effects by modifying proteins such as p53, and reducing the levels of pro-apoptotic factors, including Bax and PUMA, to prevent cell death. Additionally, it enhances E2F1 activity, which further promotes cell survival. SIRT1 also modulates Bcl-2 levels to inhibit Bax, thereby reinforcing apoptosis suppression. Through activation of FOXO3a, SIRT1 increases the levels of antioxidant enzymes, including MnSOD and CAT, thereby decreasing oxidative stress. SIRT1 also promotes autophagy via proteins such as LC3 and Agt5, thereby exerting a role in the clearance of damaged organelles. Inflammatory responses are diminished via SIRT1's deacetylation of NF-κB p65 and NLRP3, with the resultant reduction in pro-inflammatory cytokine production. SIRT1, sirtuin 1; p53, tumor protein p53; E2F1, E2F transcription factor 1; Bcl-2, B-cell lymphoma 2; FOXO3a, Forkhead box O3a; LC3, microtubule-associated protein 1A/1B-light chain 3; Agt5, autophagy protein 5; NF-κB p65, nuclear factor-κB subunit p65; NLRP3, nucleotide-binding…

Figure 2. Schematic figure, illustrating the complex association between depression and coronary heart disease. Depression leads to CHD through multiple pathways, including autonomic nervous system dysfunction, HPA axis dysfunction and inflammatory responses. These disturbances result in hormonal imbalances, such as elevated levels of aldosterone, dopamine, angiotensin II and cortisol, along with an increased heart rate and a heightening of blood pressure. Additionally, depression leads to increases in levels of pro-inflammatory cytokines such as IL-6, IL-1β and TNF-α. Hormonal imbalances resulting from autonomic dysfunction further contribute to hypertension, metabolic syndrome and left ventricular hypertrophy. These alterations, in turn, promote platelet activation, disrupt endothelial function and increase lipid deposition, all of which lead to an increased risk of CHD. CHD, coronary heart disease; HPA-axis, hypothalamic-pituitary-adrenal axis; IL-6, interleukin-6; IL-1β, interleukin 1β; TNF-α, tumor necrosis factor-α.

Figure 3. Schematic figure, illustrating the association between SIRT1 and depression. Through the regulation of PGC-1α, p53, and NF-κB, SIRT1 impacts oxidative stress and inflammation, which subsequently influences emotional and cognitive functions. These imbalances may disrupt neurogenesis and neuroplasticity, increasing the risk of depression. On the other hand, SIRT1 is able to lower the risk of depression by enhancing neurogenesis and plasticity via BDNF modulation. Additionally, the role of SIRT1 in the nucleus accumbens, where it governs neurogenesis and plasticity, helps to reduce oxidative stress and inflammation, thereby decreasing depression susceptibility. These mechanisms establish SIRT1 as a pivotal factor in both the onset and prevention of depression. SIRT1, sirtuin 1; PGC-1α, peroxisome proliferator-activated receptor γ coactivator 1-α; p53, tumor protein p53; NF-κB, nuclear factor kappa B; BDNF, brain-derived neurotrophic factor.

Figure 4. Schematic figure, illustrating the association between SIRT1 and coronary heart disease. Through the regulation of a number of cellular and molecular pathways, SIRT1 influences CHD development and progression. It regulates VSMC growth and degradation, thereby affecting atherosclerosis or plaque stability. Through its interactions with PGC-1α and LXR, SIRT1 enhances mitochondrial function and fatty acid oxidation, thereby improving insulin sensitivity and reducing the accumulation of lipids, and helping to prevent atherosclerosis. Activation of FOXO3a by SIRT1 upregulates the expression of antioxidants such as MnSOD and CAT, thereby reducing oxidative stress and supporting endothelial health, and minimizing the risk of plaque formation by reducing vascular endothelium damage. Deacetylation of NF-κB and NLRP3 by SIRT1 lowers the levels of pro-inflammatory cytokines such as IL-6, IL-1β and TNF-α, which, in turn, reduces the levels of inflammation and protects endothelial function, and collectively, these processes cause a slowing down of atherosclerosis and a lowering of the CHD risk. SIRT1, sirtuin 1; VSMCs, vascular smooth muscle cells; PGC-1α, peroxisome proliferator-activated…

Figure 5. Schematic figure, illustrating the association between SIRT1, depression and coronary heart disease. Depression increases the risk of CHD by disrupting autonomic function, increasing the level of oxidative stress and triggering inflammation, which collectively contribute to endothelial dysfunction, platelet activation and the accumulation of lipids, driving atherosclerosis. SIRT1 regulates these processes by supporting autonomic function, increasing the levels of antioxidant enzymes such as MnSOD and CAT, and decreasing the levels of pro-inflammatory cytokines. Additionally, SIRT1 modulates TGF-β1 to further mitigate cardiovascular damage, helping to lower the risk of CHD associated with depression. SIRT1, sirtuin 1; TGF-β1, transforming growth factor-β1; MnSOD, manganese superoxide dismutase; CAT, catalase; IL-6, interleukin-6; IL-1β, interleukin 1β; TNF-α, tumor necrosis factor-α; CHD, coronary heart disease.