Extract of Sheng-Mai-San Ameliorates Myocardial Ischemia-Induced Heart Failure by Modulating Ca2+-Calcineurin-Mediated Drp1 Signaling Pathways

Abstract

Sheng-Mai-San (SMS) is a well-known traditional Chinese medicine (TCM) complex prescription used to treat heart failure (HF) and angina in clinic. However, its potential therapeutic mechanisms remain unclear. The present study evaluated the cardioprotection of extract of SMS (ESMS) on myocardial ischemia (MI)-induced HF, and explored the underlying molecular mechanisms. The results demonstrated that ESMS (728.0 mg/kg) significantly attenuated MI injury-induced HF by improving cardiac function and pathological changes, decreasing lactate dehydrogenase (LDH), creatine kinase (CK) activities, and brain natriuretic peptide (BNP) levels; increasing ATPase activity; and reducing intracellular Ca2+ levels in MI-induced HF mice model. It also significantly decreased the apoptotic index. In vitro, ESMS (400 μg/mL) inhibited mitochondrial-dependent myocardial apoptosis by modulating the expression of caspase-3 and the Bcl-2/Bax ratio, and improved mitochondrial function through increasing mitochondrial membrane potential and cellular ATP content. ESMS restored intracellular Ca2+ and downregulated the expression of Calcineurin A (CnA), thus inhibiting phosphorylation of dynamin-related protein 1 (Drp1) at Ser616 and increasing phosphorylation of Drp1 at Ser637 to prevent cardiomyocyte mitochondrial fission. Above-mentioned results demonstrated ESMS suppressed mitochondrial-mediated apoptosis in oxygen glucose deprivation (OGD) injured H9c2 cardiomyocytes. These findings suggested that ESMS attenuated MI-induced HF by regulating Ca2+ homeostasis and suppressing mitochondrial mediated apoptosis through the modulation of Ca2+-calcineurin-mediated Drp1 signaling pathways. Our results provide insight into the mechanism and clinical applications of SMS and suggest a potential therapeutic strategy for HF.

Modulatory Effects of Chinese Herbal Medicines on Energy Metabolism in Ischemic Heart Diseases

“…In vitro, SMS (400 µg/mL) could improve mitochondrial function by enhancing MMP and ATP levels. Besides, SMS inhibited phosphorylation of Drp1 at Ser 616 and increased phosphorylation of Drp1 at Ser 637 in OGD-induced cardiomyocytes injury (Yang et al, 2017d). Drp1 has two major phosphorylation sites.…”

Mitochondrial Kinases and the Role of Mitochondrial Protein Phosphorylation in Health and Disease

“…Phosphorylation of DRP1 at Ser637 inhibits mitophagy and promotes mitochondrial fusion, most likely by increasing its binding to mitochondrial elongation factor 1/2 (MIEF1/2) [ 44 , 45 ]. A decrease in mitochondrial fission is also caused by the phosphorylation of DRP1 by AMPK, which plays a protective role in nervous system mitochondria, as well as by DRP1 phosphorylation by the Ca 2+ /calmodulin-dependent protein kinase (CAMK) that acts in cardiomyocytes [ 46 , 47 ]. Mitochondrial fission is promoted, on the other hand, by DRP1 phosphorylation at Ser585 by CDK5 (cyclin-dependent kinase 5) [ 48 ], by modification of Tyr266 by the Abelson tyrosine kinase (ABL) [ 22 ], and by phosphorylation at the highly conserved Ser616 by ERK1/2 (extracellular receptor kinase 1/2), which increased mitochondrial fragmentation in human pancreatic adenocarcinoma [ 49 ].…”

“…To date, protein kinases confirmed to be localized to the OMM are Ser/Thr kinases. In addition to PKA [ 83 , 84 ], JNK [ 85 ], ERK1/2 [ 86 ], p38 MAPK [ 87 ], PINK1 [ 88 ], CDK5 [ 48 ], LRRK2 [ 89 ], mTOR [ 77 ], PAK5 [ 82 ], CAMK [ 47 ] and AMPK [ 90 ], they also include cyclin-dependent kinase 11 (CDK11) [ 91 ], casein kinases 1 and 2 (CK1, CK2) [ 92 , 93 ], and three isoforms of protein kinase C (PKC α, PKC δ and PKC ε) [ 94 , 95 , 96 ]. All these kinases phosphorylate diverse mitochondrial substrates, resulting in many different alterations to organellar dynamics, protein import, metabolism, respiratory complex activity and apoptosis, all of which will be more extensively discussed in the following chapters.…”

Crosstalk between Mitochondria and Cytoskeleton in Cardiac Cells

“…However, increased mitochondrial and cytosolic Ca 2+ may lead to various pathologies and diseases, such as IRI, hypoxia-reoxygenation, arrhythmias, hypertension, heart failure, and metabolic syndrome, etc. [179,[181][182][183][184]. This can be tightly associated with multiple Ca 2+ -modulated processes, such as: mitochondria/cell swelling, changes in the interactions between cytoskeleton, mitochondria, and SR, decline of ∆Ψm, diminished mitochondrial respiratory capacity and consequent decreased cellular ATP content (energy stress), altered mitochondrial dynamics (fission-fusion balance, Drp1 signaling), increased ROS (oxidative stress), and induction of apoptosis [179,183,185].…”