Boosting autophagy in the diabetic heart: a translational perspective

Diabetes, obesity, and dyslipidemia are main risk factors that promote the development of cardiovascular diseases. These metabolic abnormalities are frequently found to be associated together in a highly morbid clinical condition called metabolic syndrome. Metabolic derangements promote endothelial dysfunction, atherosclerotic plaque formation and rupture, cardiac remodeling and dysfunction. This evidence strongly encourages the elucidation of the mechanisms through which obesity, diabetes, and metabolic syndrome induce cellular abnormalities and dysfunction in order to discover new therapeutic targets and strategies for their prevention and treatment. Numerous studies employing both dietary and genetic animal models of obesity and diabetes have demonstrated that autophagy, an intracellular system for protein degradation, is impaired in the heart under these conditions. This suggests that autophagy reactivation may represent a future potential therapeutic intervention to reduce cardiac maladaptive alterations in patients with metabolic derangements. In fact, autophagy is a critical mechanism to preserve cellular homeostasis and survival. In addition, the physiological activation of autophagy protects the heart during stress, such as acute ischemia, starvation, chronic myocardial infarction, pressure overload, and proteotoxic stress. All these aspects will be discussed in our review article together with the potential ways to reactivate autophagy in the context of obesity, metabolic syndrome, and diabetes

RASSF1A Signaling in the Heart: Novel Functions beyond Tumor Suppression

The RASSF proteins are a family of polypeptides, each containing a conserved Ras association domain, suggesting that these scaffold proteins may be effectors of activated Ras or Ras-related small GTPases. RASSF proteins are characterized by their ability to inhibit cell growth and proliferation while promoting cell death. RASSF1 isoform A is an established tumor suppressor and is frequently silenced in a variety of tumors and human cancer cell lines. However, our understanding of its function in terminally differentiated cell types, such as cardiac myocytes, is relatively nascent. Herein, we review the role of RASSF1A in cardiac physiology and disease and highlight signaling pathways that mediate its function

Editorial: Mitochondrial dysfunction and cardiovascular diseases

A deeper understanding of the molecular mechanisms underlying the development and progression of cardiovascular diseases represents a major goal in cardiovascular medicine. Mitochondrial dysfunction has emerged as major player in the development of cardiovascular diseases, with potential therapeutic implications. Mitochondrial dysfunction encompasses mitochondrial complex disruption, mitochondrial uncoupling, and cristae remodeling and swelling, which in turn cause ROS accumulation, energy stress, and cell death

Rag GTPases are cardioprotective by regulating lysosomal function.

The Rag family proteins are Ras-like small GTPases that have a critical role in amino-acid-stimulated mTORC1 activation by recruiting mTORC1 to lysosome. Despite progress in the mechanistic understanding of Rag GTPases in mTORC1 activation, little is known about the physiological function of Rag GTPases in vivo. Here we show that loss of RagA and RagB (RagA/B) in cardiomyocytes results in hypertrophic cardiomyopathy and phenocopies lysosomal storage diseases, although mTORC1 activity is not substantially impaired in vivo. We demonstrate that despite upregulation of lysosomal protein expression by constitutive activation of the transcription factor EB (TFEB) in RagA/B knockout mouse embryonic fibroblasts, lysosomal acidification is compromised owing to decreased v-ATPase level in the lysosome fraction. Our study uncovers RagA/B GTPases as key regulators of lysosomal function and cardiac protection

Mid-Septal Hypertrophy and Apical Ballooning; Potential Mechanism of Ventricular Tachycardia Storm in Patients with Hypertrophic Cardiomyopathy

Medically refractory ventricular tachycardia (VT) storm can be controlled with radiofrequency catheter ablation (RFCA), however, it may be difficult to control in some patients with hemodynamic overload. We experienced a patient with intractable VT storm controlled by hemodynamic unloading. The patient had mid-septal hypertrophic cardiomyopathy with an implantable cardioverter defibrillator (ICD) back-up. Because of the severe mid-septal hypertrophy, his left ventricle (LV) had an hourglass-like morphology and showed apical ballooning; the focus of VT was at the border of apical ballooning. Although we performed VT ablation because of electrical storm with multiple ICD shocks, VT recurred 1 hour after procedure. As the post-RFCA monomorphic VT was refractory to anti-tachycardia pacing or ICD shock, we reduced the hemodynamic overload of LV with β-blockade, hydration, and sedation. VT spontaneously stopped 1.5 hours later and the patient has remained free of VT for 24 months with β-blockade alone. In patients with VT storm refractory to antiarrhythmic drugs or RFCA, the mechanism of mechano-electrical feedback should be considered and hemodynamic unloading may be an essential component of treatment

Thioredoxin-1 maintains mechanistic target of rapamycin (mTOR) function during oxidative stress in cardiomyocytes

Thioredoxin 1 (Trx1) is a 12-kDa oxidoreductase that catalyzes thiol-disulfide exchange reactions to reduce proteins with disulfide bonds. As such, Trx1 helps protect the heart against stresses, such as ischemia and pressure overload. Mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that regulates cell growth, metabolism, and survival. We have shown previously that mTOR activity is increased in response to myocardial ischemia-reperfusion injury. However, whether Trx1 interacts with mTOR to preserve heart function remains unknown. Using a substrate-trapping mutant of Trx1 (Trx1C35S), we show here that mTOR is a direct interacting partner of Trx1 in the heart. In response to H2O2 treatment in cardiomyocytes, mTOR exhibited a high molecular weight shift in non-reducing SDS-PAGE in a 2-mercaptoethanol-sensitive manner, suggesting that mTOR is oxidized and forms disulfide bonds with itself or other proteins. The mTOR oxidation was accompanied by reduced phosphorylation of endogenous substrates, such as S6 kinase (S6K) and 4E-binding protein 1 (4E-BP1) in cardiomyocytes. Immune complex kinase assays disclosed that H2O2 treatment diminished mTOR kinase activity, indicating that mTOR is inhibited by oxidation. Of note, Trx1 overexpression attenuated both H2O2-mediated mTOR oxidation and inhibition, whereas Trx1 knockdown increased mTOR oxidation and inhibition. Moreover, Trx1 normalized H2O2-induced down-regulation of metabolic genes and stimulation of cell death, and an mTOR inhibitor abolished Trx1-mediated rescue of gene expression. H2O2-induced oxidation and inhibition of mTOR were attenuated when Cys-1483 of mTOR was mutated to phenylalanine. These results suggest that Trx1 protects cardiomyocytes against stress by reducing mTOR at Cys-1483, thereby preserving the activity of mTOR and inhibiting cell death