Cardiac-Specific Overexpression of Silent Information Regulator 1 Protects Against Heart and Kidney Deterioration in Cardiorenal Syndrome via Inhibition of Endoplasmic Reticulum Stress

Abstract

Background/Aims: Increased endoplasmic reticulum (ER) stress contributes to development of cardiorenal syndrome (CRS), and Silent Information Regulator 1 (SIRT1), a class III histone deacetylase, may have protective effects on heart and renal disease, by reducing ER stress. We aimed to determine if SIRT1 alleviates CRS through ER stress reduction. Methods: Wild type mice (n=37), mice with cardiac-specific SIRT1 knockout (n=29), or overexpression (n=29), and corresponding controls, were randomized into four groups: sham MI (myocardial infarction) +sham STNx (subtotal nephrectomy); MI+sham STNx; sham MI+STNx; and MI+STNx. To establish the CRS model, subtotal nephrectomy (5/6 nephrectomy, SNTx) and myocardial infarction (MI) (induced by ligation of the left anterior descending (LAD) coronary artery) were performed successively to establish CRS model. At week 8, the mice were sacrificed after sequential echocardiographic and hemodynamic studies, and then pathology and Western-blot analysis were performed. Results: Neither MI nor STNx alone significantly influenced the other healthy organ. However, in MI groups, STNx led to more severe cardiac structural and functional deterioration, with increased remodeling, increased BNP levels, and decreased EF, Max +dp/dt, and Max -dp/dt values than in sham MI +STNx groups. Conversely, in STNx groups, MI led to renal structural and functional deterioration, with more severe morphologic changes, augmented desmin and decreased nephrin expression, and increased BUN, SCr and UCAR levels. In MI+STNx groups, SIRT1 knockout led to more severe cardiac structural and functional deterioration, with higher Masson-staining score and BNP levels, and lower EF, FS, Max +dp/dt, and Max -dp/dt values; while SIRT1 overexpression had the opposite attenuating effects. In kidney, SIRT1 knockout resulted in greater structural and functional deterioration, as evidenced by more severe morphologic changes, higher levels of UACR, BUN and SCr, and increased desmin and TGF-β expression, while SIRT1 overexpression resulted in less severe morphologic changes and increased nephrin expression without significant influence on BUN or SCr levels. The SIRT1 knockout but not overexpression resulted in increased myocardial expression of CHOP and GRP78. Cardiac-specific SIRT1 knockout or overexpression resulted in increased or decreased renal expression of CHOP, Bax, and p53 respectively. Conclusions: Myocardial SIRT1 activation appears protective to both heart and kidney in CRS models, probably through modulation of ER stress.

Curcumin Inhibits the PERK-eIF2α-CHOP Pathway through Promoting SIRT1 Expression in Oxidative Stress-induced Rat Chondrocytes and Ameliorates Osteoarthritis Progression in a Rat Model

“…In support of our results, previous related studies have shown that SIRT1 plays a crucial part in the regulation of ER stress-related apoptosis in different cells [20–23]. Moreover, SIRT1-deficient cells are sensitive to oxidative stress [52, 53], further proving the idea that SIRT1 plays an essential role in protecting against oxidative stress and related apoptosis.…”

“…SIRT1 exerts antiapoptotic function through the deacetylation of apoptosis-inducible nonhistone proteins including P53 [17], forkhead family proteins [18], and RelA/p65 subunit of nuclear factor- κ B (NF- κ B) [19]. Previous studies verified the protective role of SIRT1 in different cells under oxidative stress and ER stress [20–23]. In osteoarthritis cartilage, research showed that the activation of SIRT1 is essential to the maintenance of articular cartilage homeostasis owing to its antiapoptotic effect [24, 25].…”

Panax Notoginseng Saponins Protect Cardiac Myocytes Against Endoplasmic Reticulum Stress and Associated Apoptosis Through Mediation of Intracellular Calcium Homeostasis

“…Numerous studies have shown that cardiac myocytes are vulnerable to cellular ER stress and contribute to the pathogenesis of several cardiovascular derangements through exposure to hyperoxidation, inflammation, apoptosis, etc. These findings have sparked interest, demonstrating a link between ER stress and cardiovascular pathogenesis, while the elevation of ER stress–associated apoptosis has been proposed to contribute to various cardiovascular diseases (Camargo et al, 2018; Chang et al, 2018; Huang et al, 2018). Hence, modulation of ER stress, especially downstream of calcium-mediated apoptotic execution pathways, becomes critical in understanding the mechanism and the development of a novel target of pathogenesis of cardiovascular diseases.…”

Methane supplementation improves graft function in experimental heart transplantation

“…31−34 More directly, as a consequence of HIF-1a expression, mRNA expression of VLDLr and the proapoptotic transcription factor CHOP are also increased, and by the end of this process, CHOP upregulates bcl-2-like protein 11 mRNA expression and activates Bax protein to translocate from the cytosol to the mitochondria. 31,35 Our results demonstrate that cold ischemia and graft storage activated all these participants, starting from higher SERCA1 protein levels reflecting an increased Ca 2+ pump function in the ER and elevated HIF-1a expression in cardiomyocytes. In addition, higher intracellular Ca 2+ can activate GSK-3b, the proapoptotic factor in the intrinsic mitochondrial apoptotic pathway.…”