Endothelial SIRT6 Is Vital to Prevent Hypertension and Associated Cardiorenal Injury Through Targeting Nkx3.2-GATA5 Signaling

Abstract

Rationale: Endothelial dysfunction is an important determinant risk factor for the development of hypertension and its complications. Thus, identification of potential therapeutic targets for preventing endothelial dysfunction has major clinical importance. Emerging evidence indicates that epigenetic modifications are closely associated with the regulation of endothelial function. Among them, HDAC (histone deacetylase)-mediated epigenetic processes in vascular homeostasis and cardiovascular disease have attracted much attention. SIRT6 (sirtuin 6) is one member of SIRTs (class III HDAC) that are highly conserved NAD + -dependent deacetylases. Objective: This study was designed to elucidate the role of SIRT6 in the pathogenesis of hypertension, discover the new targets of SIRT6, and explore related mechanisms on the regulation of endothelial function. Methods and Results: The levels of endothelial SIRT6 were significantly reduced in 2 independent hypertension models: desoxycorticosterone acetate/salt–induced and Ang II (angiotensin II)–induced hypertensive mice. Utilizing genetically engineered endothelial-specific SIRT6 knockout (Cre + /SIRT6 fl/fl ) mice, we found that endothelial-specific deletion of SIRT6 significantly enhanced blood pressure, exacerbated endothelial dysfunction and cardiorenal injury in experimental hypertension. Functionally, SIRT6 has pleiotropic protective actions in endothelial cells, which include promoting endothelium-dependent vasodilatation and vascular NO bioavailability, reducing cellular permeability, ameliorating endothelial senescence and apoptosis, and facilitating autophagy. Mechanistically, SIRT6 induced the expression of GATA5 (GATA-binding protein 5), a novel regulator of blood pressure, through inhibiting Nkx3.2 (NK3 homeobox 2) transcription by deacetylating histone H3K9 (histone H3 lysine 9), thereby regulating GATA5-mediated signaling pathways to prevent endothelial injury. Finally, we provide direct evidence for the therapeutic potential of SIRT6 in desoxycorticosterone acetate/salt–induced hypertensive mice by overexpression of SIRT6 in vivo. Conclusions: This study for the first time demonstrates that SIRT6 prevents hypertension and its complications by maintaining endothelial function. Pharmacological targeting of SIRT6 may be an innovative therapeutic strategy for treating patients with hypertension.

From embryogenesis to adulthood: Critical role for GATA factors in heart development and function

“…These findings have also been shown to be clinically relevant with the finding of two GATA5 variants associated with human hypertension. More recently, upstream regulation of GATA5 in these processes has been linked to activation by SIRT6 and resulting downregulation of the GATA5 repressor NKX2.3 . The availability of the various mouse lines with genetically modified Gata5 locus opens the door to probing the role of GATA5 in adult cardiac function and cardiovascular disease including in aortopathy and endothelial dependent diseases.…”

Elevated Serum Level of Cytokeratin 18 M65ED Is an Independent Indicator of Cardiometabolic Disorders

“…The strong correlation between serum CK18 M65ED levels and the risk for cardiometabolic disorders might be explained by the interactions among various metabolic stress inducers that are activated by nutritional surplus, inflammation, innate immune system, and gut microbiota during the induction of cell death. Under conditions of glucotoxicity, lipotoxicity, and exposure to proinflammatory cytokines or biologically active sphingolipids, cell death mediated by ER stress, 4-hydroxynonenal, and endogenous reactive oxygen species may contribute to the pathogenesis of cardiometabolic disorders [9,10,36]. Long-lasting and low-grade chronic inflammation mediated by cytokines and chemokines, which are primarily released by innate immune cells under cardiometabolic stress, is a distinguishing feature of Journal of Diabetes Research cardiometabolic disorders, and their overactive responses can directly contribute to the pathogenesis of such diseases [37][38][39].…”

“…Long-lasting and low-grade chronic inflammation mediated by cytokines and chemokines, which are primarily released by innate immune cells under cardiometabolic stress, is a distinguishing feature of Journal of Diabetes Research cardiometabolic disorders, and their overactive responses can directly contribute to the pathogenesis of such diseases [37][38][39]. For example, pancreatic β-cell apoptosis due to hyperglycemia and ER stress can contribute to the decreased β-cell mass that characterizes T2D, and the activation of inflammasomes by these harmful factors can lead to β-cell death [9]. Thus, β-cell death and cell death-associated inflammation interact with each other through innate immune receptors [9].…”

“…For example, pancreatic β-cell apoptosis due to hyperglycemia and ER stress can contribute to the decreased β-cell mass that characterizes T2D, and the activation of inflammasomes by these harmful factors can lead to β-cell death [9]. Thus, β-cell death and cell death-associated inflammation interact with each other through innate immune receptors [9]. Another explanation might be that altered microbial compositions in patients with cardiometabolic disorders may foster inflammation by producing more proinflammatory molecules such as lipopolysaccharide and peptidoglycans that can interact with host pattern recognition receptors of the innate immune system [40][41][42].…”

“…Massive beta cell death [6,7] and cell death-induced decrease in the delta cell volume and number cause T2D [8]. Endothelial apoptosis can lead to endothelial dysfunction and development of hypertension [9]. Apoptosis in response to glucose excess was observed in cardiometabolic diseases [10], and decreased myocardial levels of apoptosis were found to significantly reduce obesity-associated cardiomyopathy [11].…”