Cell-Permeable Pentapeptide V5 Inhibits Apoptosis and Enhances Insulin Secretion, Allowing Experimental Single-Donor Islet Transplantation in Mice

Rivas‐Carrillo, Jorge David; Soto-Gutiérrez, Alejandro; Navarro-Alvarez, Nalú; Noguchi, Hirofumi; Okitsu, Teru; Chen, Yong; Yuasa, Takeshi; Tanaka, Kazunori; Narushima, Michiki; Miki, Atsushi; Misawa, Haruo; Tabata, Yasuhiko; Lee, Youn-Jung; Matsumoto, Shinichi; Fox, Ira J.; Tanaka, Noriaki; Kobayashi, Naoya

doi:10.2337/db06-1679

Cited by 30 publications

(20 citation statements)

References 49 publications

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“…The present findings are in agreement with several others demonstrating an association between reduced viability and impaired insulin secretion (16,24,30,38,43,46). Indeed, the protective effect of PDTC on insulin secretion occurs in parallel with a reduction in human islet cell death.…”

Section: Discussionsupporting

confidence: 82%

SUMOylation protects against IL-1β-induced apoptosis in INS-1 832/13 cells and human islets

Hajmrle

Ferdaoussi

Plummer

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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tional modification by the small ubiquitin-like modifier (SUMO) peptides, known as SUMOylation, is reversed by the sentrin/SUMOspecific proteases (SENPs). While increased SUMOylation reduces ␤-cell exocytosis, insulin secretion, and responsiveness to GLP-1, the impact of SUMOylation on islet cell survival is unknown. Mouse islets, INS-1 832/13 cells, or human islets were transduced with adenoviruses to increase either SENP1 or SUMO1 or were transfected with siRNA duplexes to knockdown SENP1. We examined insulin secretion, intracellular Ca 2ϩ responses, induction of endoplasmic reticulum stress markers and inducible nitric oxide synthase (iNOS) expression, and apoptosis by TUNEL and caspase 3 cleavage. Surprisingly, upregulation of SENP1 reduces insulin secretion and impairs intracellular Ca 2ϩ handling. This secretory dysfunction is due to SENP1-induced cell death. Indeed, the detrimental effect of SENP1 on secretory function is diminished when two mediators of ␤-cell death, iNOS and NF-B, are pharmacologically inhibited. Conversely, enhanced SUMOylation protects against IL-1␤-induced cell death. This is associated with reduced iNOS expression, cleavage of caspase 3, and nuclear translocation of NF-B. Taken together, these findings identify SUMO1 as a novel antiapoptotic protein in islets and demonstrate that reduced viability accounts for impaired islet function following SENP1 up-regulation. islets of Langerhans; SUMOylation; inducible nitric oxide synthase; sentrin/SUMO-specific protease 1; SENP1 SMALL UBIQUITIN-RELATED MODIFIER (SUMO) peptides are involved in the posttranslational modification of numerous cellular proteins (19,20,26). SUMO modification, known as SUMOylation, occurs through a cascade of well-characterized enzymatic events that rely on the E2 conjugating enzyme Ubc9 (19,20,22). SUMOylation is made reversible by the sentrin/ SUMO-specific proteases (SENPs), which remove SUMO from target proteins (49). Due to the large number of SUMOylatable targets, the cellular outcomes of SUMO modification are diverse, ranging from the control of DNA repair to the regulation of transcription factors and plasma membrane proteins (9,10,20,28,39,42,44). SUMO1 modification has a negative impact on ␤-cell secretory function (35). Upregulation of SUMO1 decreases insulin gene expression (28, 44), glucagon-like peptide-1 (GLP-1) receptor signaling (42), and both glucose-and exendin-4-stimulated insulin secretion (10, 42), suggesting that deSUMOylation may improve secretory function. Indeed, knockdown of the SUMOylating enzyme Ubc9 enhances exendin-4-stimulated insulin secretion (42), and upregulation of the deSUMOylating enzyme SENP1 increases exocytosis from rodent ␤-cells at low glucose (10, 48). Whether this elevates insulin secretion above that stimulated by glucose is unclear, as SENP1 does not increase ␤-cell exocytosis above the levels seen with high glucose (10). Thus, while increased SUMOylation results in secretory impairment (10, 42, 48), the effect of the deSUMOylating enzyme SENP1 remains unknown.SUMOyla...

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Section: Discussionsupporting

confidence: 82%

SUMOylation protects against IL-1β-induced apoptosis in INS-1 832/13 cells and human islets

Hajmrle

Ferdaoussi

Plummer

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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“…Cellpermeable apoptosis inhibitors pentapeptides (V5 and DHMEQ) were shown to improve transplantation outcomes when used throughout the islet isolation process [184,185] . Similar improvements in yield and quality of rat and porcine islets were obtained when the tetrapeptide zDEVDFMK (caspase 3 inhibitor) was included in the enzymatic blend used to digest the pancreas (Barkai et al, unpublished data).…”

Section: Controlling Apoptosismentioning

confidence: 99%

Survival of encapsulated islets: More than a membrane story

Barkai¹,

Rotem²,

Vos³

2016

WJT

116

109

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“…Then, the pro-apoptotic gene Bax is considered to be involved in the apoptosis of isolated islets. The ratio of the Bax to the anti-apoptotic gene Bcl-2 might play important roles in the deterioration of insulin secretion and apoptosis after isolation [35][36][37]. The inhibition of Bax expression might lead to the prevention of apoptosis, the enhancement of islet viability, and the reduction of islet mass to reverse diabetes in mice [36].…”

Section: Discussionmentioning

confidence: 99%