Significance and Mechanistic Relevance Of SIRT6 mediated Endothelial Dysfunction in Cardiovascular Disease Progression

Introduction to Endothelium and Endothelial Dysfunction.

Vascular endothelium or endothelial cells (ECs) are the monolayer cells that line the inner wall of all blood vessels. Once considered as inert, is now considered as a dynamic organ lining the complete vasculature¹. The functional role of vascular Endothelium is to maintain vascular tone, atheroprotective and form a barrier for controlled migration of various substances back and forth from blood and various tissues¹. Of recent a new function associated to ECs are its ability to differentiate or transform to other cell lineages to perform functions that is not clear and yet to be established^{2, 3}. Dysfunction of ECs has been extensively studied and is known to be a critical factor for causing all type cardiovascular diseases and progression⁴. Several factors as described in Figure 1, contribute to endothelial dysfunction of which senescence, the process of permanent cell cycle arrest caused due to telomere attrition, vascular inflammation, endothelial nitric oxide synthase uncoupling which leads to accumulation of reactive oxygen and nitrogen species, impaired angiogenesis preventing development of new vasculature and impaired protein homeostasis caused due to failure of autophagy and lysosomal dysfunction are considered to play a vital role^{5, 6}. Although much is known about ECs, there is still a huge knowledge gap to understand several unknown functions and characteristics, which opens a scope for new discoveries in the field of endothelial biology.

Figure 1.

Schematic representation of endothelial dysfunction and its influence on function and mechanisms of ECs. Highlighted in green is the conclusion according to Jian Guo and colleagues. Endothelial dysfunction impairs proteostasis, eNOS functions, and angiogenesis and promotes senescence, vascular inflammation and remodeling of ECs. Several Mechanisms including regulation of Nkx3.2-GATA5 signaling, eNOS uncoupling, endothelium to mesenchymal transition (EndoMT), impaired proteostasis and EDHF have been uncovered to emphasize the importance of endothelial dysfunction and its causative role in cardiovascular diseases.

Sirtuin6 and Endothelial Dysfunction

Human Sirtuins (SIRT1–7) belong to the family of nicotinamide adenine dinucleotide (NAD+)-dependent enzymes whose main function is deacetylation⁷. Sirtuins have been well studied for their protective role in cardiovascular diseases (CVDs) including endothelial dysfunction⁷. The present report mainly focuses on the role of Sirtuin6 (SIRT6) in vascular endothelial dysfunction. SIRT6 is mainly chromatin bound and has strong association with chromatin remodeling in precise regulating H3K9 and H3K56 deacetylation^{8, 9}. The importance and implications of H3K9 and H3K56 deacetylation in regulating DNA damage and repair mechanisms is well studied and is implicated to cardiovascular disease progression and other abnormalities⁸. Transgenic SIRT6 overexpression has not only been shown to extend longevity in mice but also to perform a protective role in prevention of CVDs progression^{10, 11}. Endothelial SIRT6 has been shown to prevent endothelial dysfunction upon overexpression and when deleted accelerates endothelial dysfunction^{11, 12}. All the literature mentioned above highlight the significance of SIRT6 in positively regulating the function of vascular endothelium and CVDs through various mechanisms.

The recent manuscript ‘Endothelial SIRT6 Is Vital to Prevent Hypertension and Associated Cardiorenal Injury Through Targeting Nkx3.2-GATA5 Signaling’ by Jian Guo and colleagues emphasis the importance of endothelial SIRT6 and its preventive role in hypertension. According to the manuscript and Figure 1 (highlighted in green directions), SIRT6 prevents endothelial dysfunction by preventing H3K9 acetylation thereby triggering Nkx3.2-GATA5 signaling in pathophysiological conditions. More importantly, the authors demonstrate the importance of vascular endothelium and SIRT6 in CVDs progression and prevention.¹³.

Mechanisms for endothelial mediated CVDs

The classical and extensively studied mechanism for endothelial dysfunction is eNOS uncoupling. eNOS is a key enzyme that maintains vascular tone and endothelial function during pathophysiological conditions¹⁴. In addition to its role as a potent endogenous vasodilator, several studies have shown that nitric oxide (NO) plays a key role in opposing vascular endothelial abnormalities. Endothelial NO suppresses superoxide production and improves vascular function preventing senescence and disease phenotypes¹⁴. During pathophysiological conditions, functional eNOS is uncoupled (eNOS exists as dimer in order to synthesize NO) also called as eNOS uncoupling to produce more superoxide radicals thereby leading to endothelial dysfunction¹⁵. Function of eNOS is critical to produce NO in ECs to controls blood pressure and has numerous other vasoprotective and anti-atherosclerotic effects associated with resistance to atherosclerosis¹⁴. By contrast, suppression of NO synthesis is associated with accelerated endothelial senescence, atherosclerosis and vascular disease progression^{6, 14}. Moreover, accumulating evidence from epidemiological studies indicate that humans with impaired eNOS activity are at greater risk for major adverse cardiovascular events and mortality¹⁴. The work by Jian Guo and colleagues clearly demonstrates the role of SIRT6 in regulating eNOS function in mice aortas supporting the beneficial role of SIRT6 in preventing endothelial dysfunction. Not to ignore, endothelium-dependent hyperpolarization factor (EDHF) especially in microvasculature is another factor to regulate vascular function independent to eNOS activity¹⁶. However, the relation between SIRT6 and EDHF lacks evidence and is yet to be investigated. Several other mechanisms have been demonstrated to emphasize the important role of SIRT6 in CVD prevention. The discovery of remodeling and trans-differentiation of various cell types not only to maintain physiology but also to contribute to disease progression has bought new perspectives to scientific community. Of recent, endothelium to mesenchymal transition (EndoMT) is gaining much importance as a mechanism contribution to CVDs progression¹⁷. EndoMT, is defined as the process of transforming ECs to mesenchymal like cellular subset mainly by activating TGF-beta and BMP signaling pathways^{3, 17}. According to lineage tracing studies, performed by Cooley et al, it is clearly that endothelial remodeling indeed contributes to CVD progression which is now strengthened with more compelling evidences^{3, 17}. As discussed before, histone modifications are critical for remodeling and differentiation. Evident with the fact that SIRT6 does play a major role in regulating H3K9 and H3K56 and their involvement in vascular remodeling, an association can be established although experimental evidence is lacking which emphasizes the importance of SIRT6 in EndoMT^{9, 18}. Apart from eNOS and EndoMT, recent evidence show that lysosomal acidification and maintenance of proteostasis is another important mechanism contributing to endothelial function. For optimal functioning of lysosomes and to complete the final step of autophagic degradation of cellular waste, a pH around 4.8 is required⁵. Inability of V-ATPase to (vacuolar H+ ATPases) to acidify lysosomes prevents degradation of misfolded proteins and other cellular waste thereby impairing protein homeostasis. These phenomena leads to endothelial dysfunction and risk for cardiovascular diseases⁵. Although there is no direct evidence of SIRT6 in regulating proteostasis, it is worthwhile for the scientific community to look into this direction.

Clinical relevance of SIRT6 and Importance as a therapeutic approach to treat CVDs

The present manuscript by Jian Guo and colleagues explores a new mechanism identifying the role of SIRT6 in regulating the histone complex modification thereby preventing vascular endothelial abnormalities. Evident with the role of SIRT6 in regulating various mechanisms and causative role in CVDs, targeting SIRT6 and downstream mechanistic signaling will be a potential approach for treating CVDs and several other abnormalities. Although the consequences imposed by hyper activation of SIRT6 in human studies is not well understood, controlled overexpression of SIRT6 could be a potential therapeutic approach to treat CVDs. Interestingly, flavonoids, which are naturally occurring polyphenol compounds are known for the health benefits. Certain flavonoids like flavonols and anthocyanidins have been effectively shown to increase SIRT6 activity and may have possible beneficial effects to treat CVDs¹⁹. Hence the work by Jian Guo and colleagues it is a noteworthy contribution which adds more supporting evidence not only emphasizing the importance of SIRT6 in promoting endothelial function but also highlighting the importance of vascular endothelium and its causative role in prevention and treatment of Cardiovascular diseases. Hence targeting vascular endothelium by SIRT6 regulation may be a promising therapeutic approach for treating and prevention of CVDs.