SIRT1 Activation Attenuates the Cardiac Dysfunction Induced by Endothelial Cell-Specific Deletion of CRIF1

Abstract

The CR6-interacting factor1 (CRIF1) mitochondrial protein is indispensable for peptide synthesis and oxidative phosphorylation. Cardiomyocyte-specific deletion of CRIF1 showed impaired mitochondrial function and cardiomyopathy. We developed an endothelial cell-specific CRIF1 deletion mouse to ascertain whether dysfunctional endothelial CRIF1 influences cardiac function and is mediated by the antioxidant protein sirtuin 1 (SIRT1). We also examined the effect of the potent SIRT1 activator SRT1720 on cardiac dysfunction. Mice with endothelial cell-specific CRIF1 deletion showed an increased heart-to-body weight ratio, increased lethality, and markedly reduced fractional shortening of the left ventricle, resulting in severe cardiac dysfunction. Moreover, endothelial cell-specific CRIF1 deletion resulted in mitochondrial dysfunction, reduced ATP levels, inflammation, and excessive oxidative stress in heart tissues, associated with decreased SIRT1 expression. Intraperitoneal injection of SRT1720 ameliorated cardiac dysfunction by activating endothelial nitric oxide synthase, reducing oxidative stress, and inhibiting inflammation. Furthermore, the decreased endothelial junction-associated protein zonula occludens-1 in CRIF1-deleted mice was significantly recovered after SRT1720 treatment. Our results suggest that endothelial CRIF1 plays an important role in maintaining cardiac function, and that SIRT1 induction could be a therapeutic strategy for endothelial dysfunction-induced cardiac dysfunction.

Multifunctions of CRIF1 in cancers and mitochondrial dysfunction

“…CRIF1 deficiency downregulated SIRT1 levels and promoted transcription factor NF-kB translocation to the nucleus and decreased its inhibitor IkBa. The NF-kB pathway was then activated and continued to enhance proinflammatory cytokine expression and augment cellular inflammation (79). In a model of mice with endothelial CRIF1 deficiency, severe cardiac dysfunction and premature death could be rescued by injecting exogenously the SIRT1 activator (80).…”

“…The NF-κB pathway was then activated and continued to enhance proinflammatory cytokine expression and augment cellular inflammation ( 79 ). In a model of mice with endothelial CRIF1 deficiency, severe cardiac dysfunction and premature death could be rescued by injecting exogenously the SIRT1 activator ( 80 ). SIRT1 and SIRT3 are two important protection factors which could be downregulated by CRIF1 deficiency and potentially cause cardiovascular diseases.…”

Cognitive Impairment in Multiple Sclerosis

“…The release of reactive oxygen species (ROS) during oxidative stress can occur during the shortening of TLs and the onset of cell senescence. Oxidative stress exposure ultimately affects cell survival and mitochondrial organelle function through TL shortening and the onset of cell senescence [21,52,59,68,72,74,75,[77][78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94].…”

Cornerstone Cellular Pathways for Metabolic Disorders and Diabetes Mellitus: Non-Coding RNAs, Wnt Signaling, and AMPK

“…Oxidative stress during DM can influence cell survival, cellular organelle integrity, and pathways that affect programmed cell death [5,19,25,33,42,49,63,71,85,86,168,[180][181][182][183][184][185]. Oxidative stress occurs during the generation of ROS that can be formed by entities that include superoxide free radicals, peroxynitrite, singlet oxygen, nitric oxide, and hydrogen peroxide [80,164,[185][186][187][188][189][190][191]. With the onset of oxidative stress and the release of ROS, injury can occur to neurons [15,19,76,[191][192][193][194][195][196][197][198][199][200][201], vascular cells [33,36,38,190,[202][203][204][205]…”

“…Oxidative stress occurs during the generation of ROS that can be formed by entities that include superoxide free radicals, peroxynitrite, singlet oxygen, nitric oxide, and hydrogen peroxide [80,164,[185][186][187][188][189][190][191]. With the onset of oxidative stress and the release of ROS, injury can occur to neurons [15,19,76,[191][192][193][194][195][196][197][198][199][200][201], vascular cells [33,36,38,190,[202][203][204][205][206][207], stem cells [80,199,[208][209][210], hepatic cells [51,53,[211][212][213][214][215][216], renal cells [15,43,[217]…”