Lysine acetylation is a conserved, reversible, post-translational protein modification regulated by lysine acetyltransferases (KATs) and lysine deacetylases (KDACs; also known as histone deacetylases (HDACs)) that is involved in many cellular signalling pathways and diseases. Studies in animal models have revealed a regulatory role of reversible lysine acetylation in hypertension, vascular diseases, arrhythmia, heart failure and angiogenesis. Evidence from these studies indicates a therapeutic role of KDAC inhibitors (also known as HDAC inhibitors) in cardiovascular diseases. In this Review, we describe the diverse roles of KATs and KDACs in both the normal and the diseased heart. Among KDACs, class II and class III HDACs seem to have a protective role against both cardiac damage and vessel injury, whereas class I HDACs protect against vessel injury but have deleterious effects on the heart. These observations have important implications for the clinical utility of HDAC inhibitors as therapeutic agents for cardiovascular diseases. In addition, we summarize the latest data on nonacetylation acylations in the context of cardiovascular disease.

Lysine acetyltransferases and lysine deacetylases as targets for cardiovascular disease.

Mitochondrial dynamics and their potential as a therapeutic target.

The role of mitochondrial fission in cardiovascular health and disease

Ferroptosis is a nonapoptotic form of cell death characterized by iron-dependent accumulation of lipid hydroperoxides to lethal levels. Necroptosis, an alternative form of programmed necrosis, is regulated by receptor-interacting protein (RIP) 1 activation and by RIP3 and mixed-lineage kinase domain-like (MLKL) phosphorylation. Ferroptosis and necroptosis both play important roles in the pathological progress in ischemic stroke, which is a complex brain disease regulated by several cell death pathways. In the past few years, increasing evidence has suggested that the crosstalk occurs between necroptosis and ferroptosis in ischemic stroke. However, the potential links between ferroptosis and necroptosis in ischemic stroke have not been elucidated yet. Hence, in this review, we overview and analyze the mechanism underlying the crosstalk between necroptosis and ferroptosis in ischemic stroke. And we find that iron overload, one mechanism of ferroptosis, leads to mitochondrial permeability transition pore (MPTP) opening, which aggravates RIP1 phosphorylation and contributes to necroptosis. In addition, heat shock protein 90 (HSP90) induces necroptosis and ferroptosis by promoting RIP1 phosphorylation and suppressing glutathione peroxidase 4 (GPX4) activation. In this work, we try to deliver a new perspective in the exploration of novel therapeutic targets for the treatment of ischemic stroke.

/pdf/insight-into-crosstalk-between-ferroptosis-and-necroptosis-ao6airtym6.pdf

Insight into Crosstalk between Ferroptosis and Necroptosis: Novel Therapeutics in Ischemic Stroke

We previously demonstrated that beta II protein kinase C (βIIPKC) activity is elevated in failing hearts and contributes to this pathology. Here we report that βIIPKC accumulates on the mitochondrial outer membrane and phosphorylates mitofusin 1 (Mfn1) at serine 86. Mfn1 phosphorylation results in partial loss of its GTPase activity and in a buildup of fragmented and dysfunctional mitochondria in heart failure. βIIPKC siRNA or a βIIPKC inhibitor mitigates mitochondrial fragmentation and cell death. We confirm that Mfn1-βIIPKC interaction alone is critical in inhibiting mitochondrial function and cardiac myocyte viability using SAMβA, a rationally-designed peptide that selectively antagonizes Mfn1-βIIPKC association. SAMβA treatment protects cultured neonatal and adult cardiac myocytes, but not Mfn1 knockout cells, from stress-induced death. Importantly, SAMβA treatment re-establishes mitochondrial morphology and function and improves cardiac contractility in rats with heart failure, suggesting that SAMβA may be a potential treatment for patients with heart failure.

/pdf/a-selective-inhibitor-of-mitofusin-1-biipkc-association-16ucp8xkfc.pdf

A selective inhibitor of mitofusin 1-βIIPKC association improves heart failure outcome in rats.

Hypertension-induced cardiac apoptosis is a major contributor to early-stage heart-failure. Our previous studies have found that p53-mediated mitochondrial fission is involved in aldosterone-induced podocyte apoptosis. However, it is not clear that whether p53-induced mitochondrial fission is critical for hypertensive Angiotensin II (AngII)-induced cardiomyocyte apoptosis. In this study, we found that inhibition of the mitochondrial fission protein Drp1 (dynamin-related protein 1) by Mdivi-1 prevented cardiomyocyte apoptosis and cardiac remodeling in SHRs. In vitro we found that treatment of cultured neonatal rat cardiomyocytes with AngII induced Drp1 expression, mitochondrial fission, and apoptosis. Knockdown of Drp1 inhibited AngII-induced mitochondrial fission and cardiomyocyte apoptosis. Furthermore, AngII induced p53 acetylation. Knockdown of p53 inhibited AngII-induced Drp1 expression, mitochondrial fission, and cardiomyocyte apoptosis. Besides, we found that Sirt1 was able to reverse AngII-induced p53 acetylation and its binding to the Drp1 promoter, which subsequently inhibited mitochondrial fission and eventually attenuated cardiomyocyte apoptosis. Collectively, these results suggest that AngII degrades Sirt1 to increase p53 acetylation, which induces Drp1 expression and eventually results in cardiomyocyte apoptosis. Sirt1/p53/Drp1dependent mitochondrial fission may be a valuable therapeutic target for hypertension induced heart failure.

/pdf/mitochondrial-fission-is-required-for-angiotensin-ii-induced-jpi0992ubg.pdf

Mitochondrial Fission Is Required for Angiotensin II-Induced Cardiomyocyte Apoptosis Mediated by a Sirt1-p53 Signaling Pathway

Metalloproteinase (MMP)9 plays a pivotal role in ischemic stroke induced blood brain barrier (BBB) disruption. Correlation between HSP90 and MMP9 in several diseases prompted us to evaluate the efficacy of HSP90 inhibition as a novel approach to protect BBB integrity in ischemic stroke. ELISA was used to detect HSP90α and MMP9 in serum samples of stroke patients, which showed that HSP90α significantly correlated with MMP9 among 63 serum samples of stroke patients. Male C57/BL6 mice were pretreated with 17-Dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) or vehicle before being subjected to transient occlusion of middle cerebral artery and reperfusion (MCAO). Infarction, neurological scores, Evans blue (EB) extravasation, inflammatory responses and tight junction protein expression were examined 24 h after MCAO. We also investigated if 17-DMAG protected BBB integrity by suppressing inflammation and MMP9 activation. Oxygen glucose deprivation (OGD) was performed on bEnd.3 cells to explore the mechanisms of HSP90 inhibition in inhibiting MMP9. The results demonstrated that infarct volume was reduced in 17-DMAG-treated mice compared to control group following MCAO. Neurological outcomes were greatly improved in 17-DMAG-treated mice. Inflammatory responses, MMP9 activity and EB extravasation were decreased by 17-DMAG. In addition, 17-DMAG inhibited nuclear factor kappa B (NF-κB) activation following MCAO. Furthermore, HSP90 inhibition decreased NF-κB dependent MMP9 expression in bEnd.3 after OGD /reoxygenation. These findings suggested that HSP90 could be a novel therapeutic target in BBB breakdown during ischemic stroke. As several HSP90 inhibitors are in clinical trials for cancer, these findings have translational implications.

Heat shock protein 90 inhibition by 17-Dimethylaminoethylamino-17-demethoxygeldanamycin protects blood-brain barrier integrity in cerebral ischemic stroke.

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Mitochondrial Fission Is Required for Angiotensin II-Induced Cardiomyocyte Apoptosis Mediated by a Sirt1-p53 Signaling Pathway

Heat shock protein 90 inhibition by 17-Dimethylaminoethylamino-17-demethoxygeldanamycin protects blood-brain barrier integrity in cerebral ischemic stroke.