bims-hafaim 2023-03-26 papers

Issue of 2023–03–26
three papers selected by
Kyle McCommis, Saint Louis University

Cardiovasc Res. 2023 Mar 23. pii: cvad040. [Epub ahead of print]

VEGF-B hypertrophy predisposes to transition from diastolic to systolic heart failure in hypertensive rats.

AIMS: Cardiac energy metabolism is centrally involved in heart failure (HF), although the direction of the metabolic alterations is complex and likely dependent on the particular stage of HF progression. Vascular endothelial growth factor B (VEGF-B) has been shown to modulate metabolic processes and to induce physiological cardiac hypertrophy; thus, it could be cardioprotective in the failing myocardium. This study investigates the role of VEGF-B in cardiac proteomic and metabolic adaptation in HF during aldosterone and high-salt hypertensive challenges.
METHODS AND RESULTS: Male rats overexpressing the cardiac-specific VEGF-B transgene (VEGF-B TG) were treated for 3 or 6 weeks with deoxycorticosterone-acetate combined with a high-salt (HS) diet (DOCA + HS) to induce hypertension and cardiac damage. Extensive longitudinal echocardiographic studies of HF progression were conducted, starting at baseline. Sham-treated rats served as controls. To evaluate the metabolic alterations associated with HF, cardiac proteomics by mass spectrometry was performed. Hypertrophic non-treated VEGF-B TG hearts demonstrated high oxygen and adenosine triphosphate (ATP) demand with early onset of diastolic dysfunction. Administration of DOCA + HS to VEGF-B TG rats for 6 weeks amplified the progression from cardiac hypertrophy to HF, with a drastic drop in heart ATP concentration. Dobutamine stress echocardiographic analyses uncovered a significantly impaired systolic reserve. Mechanistically, the hallmark of the failing TG heart was an abnormal energy metabolism with decreased mitochondrial ATP, preceding the attenuated cardiac performance and leading to systolic HF.
CONCLUSIONS: This study shows that the VEGF-B TG accelerates metabolic maladaptation which precedes structural cardiomyopathy in experimental hypertension and ultimately leads to systolic HF.

Keywords: Aldosterone; Cardiac hypertrophy; Heart failure; Metabolism; Salt; VEGF-B

DOI: https://doi.org/10.1093/cvr/cvad040

Biomed Pharmacother. 2023 Mar 21. pii: S0753-3322(23)00112-9. [Epub ahead of print]161 114324

GLUT4 mediates the protective function of gastrodin against pressure overload-induced cardiac hypertrophy.

Miao Zhang, Yanzhen Tan, Yujie Song, Min Zhu, Bing Zhang, Cheng Chen, Yingying Liu, Lei Shi, Jun Cui, Wenju Shan, Zipei Jia, Lele Feng, Guojie Cao, Wei Yi, Yang Sun.

Gastrodia elata exhibits extensive pharmacological activity; its extract gastrodin (GAS) has been used clinically to treat cardiovascular diseases. In the present study, we examined the effect of GAS in a mice model of pathological cardiac hypertrophy, which was induced using transverse aortic constriction (TAC). Male C57BL/6 J mice underwent either TAC or sham surgery. GAS was administered post-surgically for 6 weeks and significantly improved the deterioration of cardiac contractile function caused by pressure overload, cardiac hypertrophy, and fibrosis in mice. Treatment with GAS for 6 weeks upregulated myosin heavy chain α and down-regulated myosin heavy chain β and atrial natriuretic peptide, while insulin increased the effects of GAS against cardiac hypertrophy. In vitro studies showed that GAS could also protect phenylephrine-induced cardiomyocyte hypertrophy, and these effects were attenuated by BAY-876, and increased by insulin. Taken together, our results suggest that the anti-hypertrophic effect of gastrodin depends on its entry into cardiomyocytes through GLUT4.

Keywords: Cardiac hypertrophy; GLUT4; Gastrodin

DOI: https://doi.org/10.1016/j.biopha.2023.114324

Metabolism. 2023 Mar 20. pii: S0026-0495(23)00154-3. [Epub ahead of print] 155551

Syntaxin17 contributes to obesity cardiomyopathy through promoting mitochondrial Ca2+ overload in a Parkin-MCUb-dependent manner.

Haixia Xu, Wenjun Yu, Mingming Sun, Yaguang Bi, Ne N Wu, Yuan Zhou, Qi Yang, Mengjiao Zhang, Junbo Ge, Yingmei Zhang, Jun Ren.

OBJECTIVE: Uncorrected obesity is accompanied by unfavorable structural and functional changes in the heart, known as obesity cardiomyopathy. Recent evidence has revealed a crucial role for mitochondria-associated endoplasmic reticulum membranes (MAMs) in obesity-induced cardiac complication. Syntaxin 17 (STX17) serves as a scaffolding molecule localized on MAMs although its role in obesity heart complication remains elusive.
METHODS AND MATERIALS: This study examined the role of STX17 in MAMs and mitochondrial Ca2+ homeostasis in HFD-induced obesity cardiomyopathy using tamoxifen-induced cardiac-specific STX17 knockout (STX17cko) and STX17 overexpression mice using intravenously delivered recombinant adeno-associated virus serotype-9 (AAV9-cTNT-STX17).
RESULTS: STX17 levels were significantly elevated in plasma from obese patients and heart tissues of HFD-fed mice. Our data revealed that cardiac STX17 knockout alleviated cardiac remodeling and dysfunction in obese hearts without eliciting any notable effect itself, while STX17 overexpression aggravated cardiac dysfunction in obese mice. STX17 deletion and STX17 overexpression annihilated and aggravated, respectively, HFD-induced oxidative stress (O2- production) and mitochondrial injury in the heart. Furthermore, STX17 transfection facilitated obesity-induced MAMs formation in cardiomyocytes and evoked excess mitochondrial Ca2+ influx, dependent upon interaction with mitochondrial Ca2+ uniporter dominant negative β (MCUb) through Habc domain. Our data also suggested that STX17 promoted ubiquitination and degradation of MCUb through the E3 ligase parkin in the face of palmitate challenging.
CONCLUSION: Taken together, our results identified a novel role for STX17 in facilitating obesity-induced MAMs formation, and subsequently mitochondrial Ca2+ overload, mitochondrial O2- accumulation, lipid peroxidation, resulting in cardiac impairment. Our findings denoted therapeutic promises of targeting STX17 in obesity.

Keywords: MAMs; MCUb; Mitochondrial Ca(2+) overload; Obesity cardiomyopathy; Syntaxin 17

DOI: https://doi.org/10.1016/j.metabol.2023.155551