bims-hafaim 2022-09-11 papers

Issue of 2022‒09‒11
four papers selected by
Kyle McCommis
Saint Louis University

JACC Basic Transl Sci. 2022 Aug;7(8): 779-796

Parkin Insufficiency Accentuates High-Fat Diet-Induced Cardiac Remodeling and Contractile Dysfunction Through VDAC1-Mediated Mitochondrial Ca2+ Overload.

Ne N Wu, Yaguang Bi, Amir Ajoolabady, Fei You, James Sowers, Qiurong Wang, Asli F Ceylan, Yingmei Zhang, Jun Ren.

Mitochondrial Ca2+ overload contributes to obesity cardiomyopathy, yet mechanisms that directly regulate it remain elusive. The authors investigated the role of Parkin on obesity-induced cardiac remodeling and dysfunction in human hearts and a mouse model of 24-week high-fat diet (HFD) feeding. Parkin knockout aggravated HFD-induced cardiac remodeling and dysfunction, mitochondrial Ca2+ overload, and apoptosis without affecting global metabolism, blood pressure, and aortic stiffness. Parkin deficiency unmasked HFD-induced decline in voltage-dependent anion channel (VDAC) type 1 degradation through the ubiquitin-proteasome system but not other VDAC isoforms or mitochondrial Ca2+ uniporter complex. These data suggest that Parkin-mediated proteolysis of VDAC type 1 is a promising therapeutic target for obesity cardiomyopathy.

Keywords: AMCM, adult murine cardiomyocyte; BP, blood pressure; Ca2+ overload; HFD, high-fat diet; LFD, low-fat diet; LV, left ventricular; MCU, mitochondrial Ca2+ uniporter; PA, palmitic acid; Parkin; ROS, reactive oxygen species; TR90, time to 90% relengthening; VDAC, voltage-dependent anion channel; VDAC1; WT, wild-type; heart; high-fat diet; mPTP, mitochondrial permeability transition pore; mitochondria

DOI: https://doi.org/10.1016/j.jacbts.2022.03.007

Mediators Inflamm. 2022 ;2022 8373389

Nr2f2 Overexpression Aggravates Ferroptosis and Mitochondrial Dysfunction by Regulating the PGC-1α Signaling in Diabetes-Induced Heart Failure Mice.

Weilun Miao, Mengli Chen, Minglong Chen, Chang Cui, Yue Zhu, Xinping Luo, Bangwei Wu.

Diabetes is well recognized to increase the risk of heart failure, which is associated with higher mortality and morbidity. It is important for the development of novel therapeutic methods targeting heart failure in diabetic patients. Ferroptosis, an iron-dependent regulated cell death, has been implicated in the progression of diabetes-induced heart failure (DIHF). This study was designed to investigate the contribution of Nr2f2 to the activation of ferroptosis and mitochondrial dysfunction in DIHF. We established a diabetic model by a high-fat feeding diet combined with an intraperitoneal injection of streptozotocin. After 16 weeks, Nr2f2 expression was increased in heart tissue of DIHF mice. In vivo, DIHF mice overexpressing Nr2f2 (AAV9-cTNT-Nr2f2) exhibited severe heart failure and enhanced cardiac ferroptosis compared with DIHF control mice (AAV9-cTNT-ctrl), accompanied by mitochondrial dysfunction and aggravated oxidative stress reaction. In vitro, Nr2f2 knockdown ameliorated ferroptosis and mitochondrial dysfunction by negatively regulating PGC-1α, a crucial metabolic regulator. PGC-1α knockdown counteracted the protective effect of Nr2f2 knockdown. These data suggest that Nr2f2 promotes heart failure and ferroptosis in DIHF by modulating the PGC-1α signaling. Our study provides a new idea for the treatment of diabetes-induced heart failure.

DOI: https://doi.org/10.1155/2022/8373389

BMC Med. 2022 09 07. 20(1): 309

Dapagliflozin attenuates diabetes-induced diastolic dysfunction and cardiac fibrosis by regulating SGK1 signaling.

Seul-Gee Lee, Darae Kim, Jung-Jae Lee, Hyun-Ju Lee, Ro-Kyung Moon, Yong-Joon Lee, Seung-Jun Lee, Oh-Hyun Lee, Choongki Kim, Jaewon Oh, Chan Joo Lee, Yong-Ho Lee, Seil Park, Ok-Hee Jeon, Donghoon Choi, Geu-Ru Hong, Jung-Sun Kim.

BACKGROUND: Recent studies have reported improved diastolic function in patients administered sodium-glucose cotransporter 2 inhibitors (SGLT2i). We aimed to investigate the effect of dapagliflozin on left ventricular (LV) diastolic function in a diabetic animal model and to determine the molecular and cellular mechanisms underlying its function.METHODS: A total of 30 male New Zealand white rabbits were randomized into control, diabetes, or diabetes+dapagliflozin groups (n = 10/per each group). Diabetes was induced by intravenous alloxan. Cardiac function was evaluated using echocardiography. Myocardial samples were obtained for histologic and molecular evaluation. For cellular evaluation, fibrosis-induced cardiomyoblast (H9C2) cells were obtained, and transfection was performed for mechanism analysis (serum and glucocorticoid-regulated kinase 1 (SGK1) signaling analysis).
RESULTS: The diabetes+dapagliflozin group showed attenuation of diastolic dysfunction compared with the diabetes group. Dapagliflozin inhibited myocardial fibrosis via inhibition of SGK1 and epithelial sodium channel (ENaC) protein, which was observed both in myocardial tissue and H9C2 cells. In addition, dapagliflozin showed an anti-inflammatory effect and ameliorated mitochondrial disruption. Inhibition of SGK1 expression by siRNA decreased and ENaC and Na+/H+ exchanger isoform 1 (NHE1) expression was confirmed as significantly reduced as siSGK1 in the diabetes+dapagliflozin group.
CONCLUSIONS: Dapagliflozin attenuated left ventricular diastolic dysfunction and cardiac fibrosis via regulation of SGK1 signaling. Dapagliflozin also reduced macrophages and inflammatory proteins and ameliorated mitochondrial disruption.

Keywords: Diabetes mellitus; Heart failure; Left ventricular diastolic function; Sodium-glucose cotransporter 2 inhibitor

DOI: https://doi.org/10.1186/s12916-022-02485-z

J Clin Med. 2022 Aug 26. pii: 5027. [Epub ahead of print]11(17):

Factors Associated with Recurrent Heart Failure during Incorporating SGLT2 Inhibitors in Patients Hospitalized for Acute Decompensated Heart Failure.

Masaki Nakagaito, Teruhiko Imamura, Shuji Joho, Ryuichi Ushijima, Makiko Nakamura, Koichiro Kinugawa.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce the risk of hospitalization for heart failure (HF) or death from cardiovascular causes among patients with chronic HF. However, little is known about the specific factors associated with clinical events during SGLT2i therapy in patients hospitalized for acute decompensated heart failure (ADHF).METHODS: Consecutive patients who were hospitalized for ADHF and received SGLT2i during the index hospitalization between February 2016 and April 2021 were retrospectively evaluated. We investigated the factors associated with recurrent hospitalization for HF during the SGLT2i therapy.
RESULTS: A total of 143 patients (median age 73 years, 92 men) were included. Estimated glomerular filtration rate (eGFR) was negatively associated with a primary endpoint with a hazard ratio of 0.94 (95% confidence interval 0.90-0.98, p = 0.007). Those with lower eGFR < 40.9 mL/min/1.73 m2 (n = 47) had significantly lower freedom from HF hospitalization during 1-year therapeutic period (73% versus 94%, p = 0.005).
CONCLUSIONS: Among patients who initiated medical therapy incorporating SGLT2i during the hospitalization for ADHF, a lower eGFR at baseline was associated with a recurrent hospitalization for HF. Early administration of SGLT2i prior to deterioration of renal function would be highly recommended to enjoy greater benefit from SGLT2i.

Keywords: diabetes mellitus; ejection fraction; heart failure; renal function

DOI: https://doi.org/10.3390/jcm11175027