bims-hafaim 2021-07-04 papers

Issue of 2021–07–04
four papers selected by
Kyle McCommis, Saint Louis University

Eur J Pharmacol. 2021 Jun 24. pii: S0014-2999(21)00436-2. [Epub ahead of print]906 174283

PEX5 prevents cardiomyocyte hypertrophy via suppressing the redox-sensitive signaling pathways MAPKs and STAT3.

Minghui Wang, Jingyan Li, Yanqing Ding, Sidong Cai, Zhuoming Li, Peiqing Liu.

Peroxisomal biogenesis factor 5 (PEX5) is a member of peroxisome biogenesis protein family which serves as a shuttle receptor for the import of peroxisome matrix protein. The function of PEX5 on cardiomyocyte hypertrophy remained to be elucidated. Our study demonstrated that the protein expression level of PEX5 was declined in primary neonatal rat cardiomyocytes treated with phenylephrine (PE) and hearts from cardiac hypertrophic rats induced by abdominal aortic constriction (AAC). Overexpression of PEX5 alleviated cardiomyocyte hypertrophy induced by PE, while silencing of PEX5 exacerbated cardiomyocyte hypertrophy. PEX5 improved redox imbalance by decreasing cellular reactive oxygen species level and preserving peroxisomal catalase. Moreover, PEX5 knockdown aggravated PE-induced activation of redox-sensitive signaling pathways, including mitogen-activated protein kinase (MAPK) pathway and signal transducer and activator of transcription 3 (STAT3); whereas PEX5 overexpression suppressed activation of MAPK and STAT3. But PEX5 did not affect PE-induced phosphorylation of mammalian target of rapamycin (mTOR). In conclusion, the present study suggests that PEX5 protects cardiomyocyte against hypertrophy via regulating redox homeostasis and inhibiting redox-sensitive signaling pathways MAPK and STAT3.

Keywords: Cardiomyocyte hypertrophy; MAPK; PEX5; STAT3; mTOR

DOI: https://doi.org/10.1016/j.ejphar.2021.174283

Eur Heart J Cardiovasc Pharmacother. 2021 Jul 02. pii: pvab053. [Epub ahead of print]

Cardiovascular Outcomes with GLP-1 Receptor Agonists Versus SGLT-2 Inhibitors in Patients with Type 2 Diabetes.

Caroline H Nørgaard, Liis Starkopf, Thomas A Gerds, Peter Vestergaard, Anders N Bonde, Emil Fosbøl, Lars Køber, Nathan D Wong, Christian Torp-Pedersen, Christina J-Y Lee.

AIMS: We examined cardiovascular outcomes associated with initiation of GLP-1RA versus SGLT-2i treatment in a real-world setting among patients with type 2 diabetes.
METHODS AND RESULTS: This Danish nationwide registry-based cohort study included patients with type 2 diabetes with a first ever prescription of either GLP-1RA or SGLT-2i from 2013 through 2015 with follow-up until end of 2018. All analyses were standardized with respect to age, sex, diabetes duration, comorbidity, and comedication. The main outcome was a composite of cardiovascular death, myocardial infarction, and stroke. Furthermore, the components of the composite outcome and hospitalization for heart failure were evaluated. Standardized average 3-year risks of outcomes and differences thereof were estimated using doubly robust estimation combining cause-specific Cox regression with propensity score regression. We identified 8,913 new users of GLP-1RA and 5,275 new users of SGLT-2i. The standardized 3-year risk associated with initiating GLP-1RA and SGLT-2i, respectively, was for the composite cardiovascular outcome, 5.6% (95% confidence interval (CI): 5.2-6.1) versus 5.6% (95% CI: 4.8-6.3); cardiovascular mortality, 1.6% (95% CI: 1.3-1.9) versus 1.5% (95% CI: 1.1-1.8); hospitalization for heart failure, 1.7% (95% CI: 1.5-2.0) versus 1.8% (95% CI: 1.2-2.5); myocardial infarction, 2.1% (95% CI: 1.8-2.4) versus 2.1% (95% CI: 1.5-2.6); and stroke, 2.5% (95% CI: 2.2-2.9) versus 2.6% (95% CI: 2.2-3.1).
CONCLUSION: In this nationwide study of patients with type 2 diabetes, initiating GLP-1RA versus SGLT-2i was not found to be associated with significant differences in cardiovascular risk.

Keywords: Cardiovascular mortality; GLP-1RA; Hospitalization for heart failure; Major adverse cardiovascular events; Myocardial infarction; SGLT-2i; Stroke; Type 2 diabetes

DOI: https://doi.org/10.1093/ehjcvp/pvab053

Oxid Med Cell Longev. 2021 ;2021 6617816

RIPK3-Mediated Necroptosis in Diabetic Cardiomyopathy Requires CaMKII Activation.

Yun Chen, Xinshuai Li, Yuyun Hua, Yue Ding, Guoliang Meng, Wei Zhang.

Activation of Ca2+/calmodulin-dependent protein kinase (CaMKII) has been proved to play a vital role in cardiovascular diseases. Receptor-interaction protein kinase 3- (RIPK3-) mediated necroptosis has crucially participated in cardiac dysfunction. The study is aimed at investigating the effect as well as the mechanism of CaMKII activation and necroptosis on diabetic cardiomyopathy (DCM). Wild-type (WT) and the RIPK3 gene knockout (RIPK3-/-) mice were intraperitoneally injected with 60 mg/kg/d streptozotocin (STZ) for 5 consecutive days. After 12 w of feeding, 100 μL recombinant adenovirus solution carrying inhibitor 1 of protein phosphatase 1 (I1PP1) gene was injected into the caudal vein of mice. Echocardiography, myocardial injury, CaMKII activity, necroptosis, RIPK1 expression, mixed lineage kinase domain-like protein (MLKL) phosphorylation, and mitochondrial ultrastructure were measured. The results showed that cardiac dysfunction, CaMKII activation, and necroptosis were aggravated in streptozotocin- (STZ-) stimulated mice, as well as in (Lepr) KO/KO (db/db) mice. RIPK3 deficiency alleviated cardiac dysfunction, CaMKII activation, and necroptosis in DCM. Furthermore, I1PP1 overexpression reversed cardiac dysfunction, myocardial injury and necroptosis augment, and CaMKII activity enhancement in WT mice with DCM but not in RIPK3-/- mice with DCM. The present study demonstrated that CaMKII activation and necroptosis augment in DCM via a RIPK3-dependent manner, which may provide therapeutic strategies for DCM.

DOI: https://doi.org/10.1155/2021/6617816

Biochim Biophys Acta Mol Basis Dis. 2021 Jun 29. pii: S0925-4439(21)00141-1. [Epub ahead of print] 166208

Mitochondrial function, dynamics and quality control in the pathophysiology of HFpEF.

Andrea Del Campo, Gonzalo Perez, Pablo F Castro, Valentina Parra, Hugo E Verdejo.

Heart failure (HF) is one of the leading causes of hospitalization for the adult population and a major cause of mortality worldwide. The HF syndrome is characterized by the heart's inability to supply the cardiac output required to meet the body's metabolic requirements or only at the expense of elevated filling pressures. HF without overt impairment of left ventricular ejection fraction (LVEF) was initially labeled as "diastolic HF" until recognizing the coexistence of both systolic and diastolic abnormalities in most cases. Acknowledging these findings, the preferred nomenclature is HF with preserved EF (HFpEF). This syndrome primarily affects the elderly population and is associated with a heterogeneous overlapping of comorbidities that makes its diagnosis challenging. Despite extensive research, there is still no evidence-based therapy for HFpEF, reinforcing the need for a thorough understanding of the pathophysiology underlying its onset and progression. The role of mitochondrial dysfunction in developing the pathophysiological changes that accompany HFpEF onset and progression (low-grade systemic inflammation, oxidative stress, endothelial dysfunction, and myocardial remodeling) has just begun to be acknowledged. This review summarizes our current understanding of the participation of the mitochondrial network in the pathogenesis of HFpEF, with particular emphasis on the signaling pathways involved, which may provide future therapeutic targets.

Keywords: Heart failure with preserved ejection fraction; Mitochondrial dynamics; Mitochondrial metabolism; Mitophagy

DOI: https://doi.org/10.1016/j.bbadis.2021.166208