Front Cardiovasc Med 2021 Mar 30;8:658400.
Therapeutic Potential of Quercetin to Alleviate Endothelial Dysfunction in Age-Related Cardiovascular Diseases
Olina Dagher 1 2 3, Pauline Mury 3, Nathalie Thorin-Trescases 3, Pierre Emmanuel Noly 2 3, Eric Thorin 2 3, Michel Carrier 2 3
1 Department of Cardiac Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
2 Department of Surgery, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada.
3 Center for Research, Montreal Heart Institute, Montreal, QC, Canada.
The vascular endothelium occupies a catalog of functions that contribute to the homeostasis of the cardiovascular system. It is a physically active barrier between circulating blood and tissue, a regulator of the vascular tone, a biochemical processor and a modulator of coagulation, inflammation, and immunity. Given these essential roles, it comes to no surprise that endothelial dysfunction is prodromal to chronic age-related diseases of the heart and arteries, globally termed cardiovascular diseases (CVD). An example would be ischemic heart disease (IHD), which is the main cause of death from CVD. We have made phenomenal advances in treating CVD, but the aging endothelium, as it senesces, always seems to out-run the benefits of medical and surgical therapies. Remarkably, many epidemiological studies have detected a correlation between a flavonoid-rich diet and a lower incidence of mortality from CVD. Quercetin, a member of the flavonoid class, is a natural compound ubiquitously found in various food sources such as fruits, vegetables, seeds, nuts, and wine. It has been reported to have a wide range of health promoting effects and has gained significant attention over the years. A growing body of evidence suggests quercetin could lower the risk of IHD by mitigating endothelial dysfunction and its risk factors, such as hypertension, atherosclerosis, accumulation of senescent endothelial cells, and endothelial-mesenchymal transition (EndoMT). In this review, we will explore these pathophysiological cascades and their interrelation with endothelial dysfunction. We will then present the scientific evidence to quercetin’s anti-atherosclerotic, anti-hypertensive, senolytic, and anti-EndoMT effects. Finally, we will discuss the prospect for its clinical use in alleviating myocardial ischemic injuries in IHD.
Keywords: aging; atherosclerosis; endothelial (dys)function; flavonoids; hypertension; ischemia-reperfusion; quercetin; senescence.
Figure 1 Schematic representation of the proposed connections between senescence, hypertension, atherosclerosis, and endothelial dysfunction. Normal aging and deleterious stimuli induce senescence in endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and foam cells. Accumulation of these senescent cells favors a pro-inflammatory state of the vascular bed through the senescence-associated secretory pathway (SASP). In turn, the SASP promotes pathological changes leading to the development of hypertension and atherosclerosis. In a feedback manner, hypertension and atherosclerosis induce more stressors to an already dysfunctional and senescent vessel wall. This vicious circle translates into endothelial dysfunction and, eventually, ischemic heart disease. Other causal pathways of endothelial dysfunction include hyperglycemia, insulin resistance, abnormal endothelial-to-mesenchymal transition (EndoMT), genetic predisposition and detrimental lifestyle habits such as smoking. ET-1, endothelin-1; MMP, matrix metalloproteases; NO, nitric-oxide; RAAS, renin–angiotensin–aldosterone system; ROS, reactive oxygen species.
Figure 5 Schematic representation of the endothelial and, by extension, myocardial protective effects of quercetin. These allow quercetin to act as a primary, secondary and tertiary preventive measure against cardiovascular diseases. AATK: apoptosis-associated tyrosine kinase; ACE: angiotensin-converting enzyme; AngII, angiotensin II; BK, big K, large-conductance Ca2+-sensitive K+ channels; CAV-1, caveolin-1; CDKN2A, p16, cyclin-dependent kinase inhibitor 2A; CK-MB, creatinine kinase-MB; EndoMT, endothelial-to-mesenchymal transition; ET-1, endothelin-1; IGFBP3, insulin-like growth factor binding protein-3; eNOS, endothelial nitric oxide synthase; NFκB, nuclear factor-kappa B; NO, nitric oxide; ox-LDLs, oxidized low density lipoproteins; Fyn, Src family 59 kDa non-receptor protein tyrosine-kinase; LAT, linker for activation of T cells; LTCCs, L-type Ca2+ channels; LVEDP, left ventricular end-diastolic pressure; LVEF, left ventricular ejection fraction; LVSP, left ventricular systolic pressure; MMPs, matrix metalloproteases; PAI-1, plasminogen-activated inhibitor-1; PCSK9, proprotein convertase subtilisin/kexin type 9; PI3K, phosphatidylinositol-4,5-bisphosphate 3 kinase; PLCγ2, phospholipase Cγ2; SCFAs, short-chain fatty acids; ROS, reactive oxygen species; SASP, senescence-associated secretory phenotype; SIRT1, sirtuin-1, nicotinamide adenine dinucleotide [NAD(+)]-dependent protein deacetylase; SOD, superoxide dismutase; TGF-β, transforming growth factor beta; VGKCs, voltage-gated K+ channels.
“In conclusion, quercetin represents a promising natural compound that appears to satisfy all the requirements to develop a nutraceutical against endothelial dysfunction. There is a pressing need for well-designed clinical trials that explore its intriguing potential for senolytic therapy and myocardial protection.”