Mitophagy modulation for the treatment of cardiovascular diseases.

BACKGROUND: Defects of mitophagy, the selective form of autophagy for mitochondria, are commonly observed in several cardiovascular diseases and represent the main cause of mitochondrial dysfunction. For this reason, mitophagy has emerged as a novel and potential therapeutic target. METHODS: In this review, we discuss current evidence about the biological significance of mitophagy in relevant preclinical models of cardiac and vascular diseases, such as heart failure, ischemia/reperfusion injury, metabolic cardiomyopathy and atherosclerosis. RESULTS: Multiple studies have shown that cardiac and vascular mitophagy is an adaptive mechanism in response to stress, contributing to cardiovascular homeostasis. Mitophagy defects lead to cell death, ultimately impairing cardiac and vascular function, whereas restoration of mitophagy by specific compounds delays disease progression. CONCLUSIONS: Despite previous efforts, the molecular mechanisms underlying mitophagy activation in response to stress are not fully characterized. A comprehensive understanding of different forms of mitophagy active in the cardiovascular system is extremely important for the development of new drugs targeting this process. Human studies evaluating mitophagy abnormalities in patients at high cardiovascular risk also represent a future challenge.

Role of autophagy in ischemic stroke: insights from animal models and preliminary evidence in the human disease.

Stroke represents a main cause of death and permanent disability worldwide. The molecular mechanisms underlying cerebral injury in response to the ischemic insults are not completely understood. In this article, we summarize recent evidence regarding the role of autophagy in the pathogenesis of ischemic stroke by reviewing data obtained in murine models of either transient or permanent middle cerebral artery occlusion, and in the stroke-prone spontaneously hypertensive rat. Few preliminary observational studies investigating the role of autophagy in subjects at high cerebrovascular risk and in cohorts of stroke patients were also reviewed. Autophagy plays a dual role in neuronal and vascular cells by exerting both protective and detrimental effects depending on its level, duration of stress and type of cells involved. Protective autophagy exerts adaptive mechanisms which reduce neuronal loss and promote survival. On the other hand, excessive activation of autophagy leads to neuronal cell death and increases brain injury. In conclusion, the evidence reviewed suggests that a proper manipulation of autophagy may represent an interesting strategy to either prevent or reduce brain ischemic injury.

Molecular mechanisms of naringenin modulation of mitochondrial permeability transition acting on F1FO-ATPase and counteracting saline load-induced injury in SHRSP cerebral endothelial cells.

Naringenin (NRG) was characterized for its ability to counteract mitochondrial dysfunction which is linked to cardiovascular diseases. The F1FO-ATPase can act as a molecular target of NRG. The interaction of NRG with this enzyme can avoid the energy transmission mechanism of ATP hydrolysis, especially in the presence of Ca2+ cation used as cofactor. Indeed, NRG was a selective inhibitor of the hydrophilic F1 domain displaying a binding site overlapped with quercetin in the inside surface of an annulus made by the three α and the three ß subunits arranged alternatively in a hexamer. The kinetic constant of inhibition suggested that NRG preferred the enzyme activated by Ca2+ rather than the F1FO-ATPase activated by the natural cofactor Mg2+. From the inhibition type mechanism of NRG stemmed the possibility to speculate that NRG can prevent the activation of F1FO-ATPase by Ca2+. The event correlated to the protective role in the mitochondrial permeability transition pore opening by NRG as well as to the reduction of ROS production probably linked to the NRG chemical structure with antioxidant action. Moreover, in primary cerebral endothelial cells (ECs) obtained from stroke prone spontaneously hypertensive rats NRG had a protective effect on salt-induced injury by restoring cell viability and endothelial cell tube formation while also rescuing complex I activity.

Towards the Fifth Pillar for the Treatment of Heart Failure with Reduced Ejection Fraction: Vericiguat in Older and Complex Patients.

Heart failure with reduced ejection fraction (HFrEF) represents an emerging epidemic, particularly affecting frail, older, and multimorbid patients. Current therapy for the management of HFrEF includes four different classes of disease-modifying drugs, commonly referred to as 'four pillars', which target the neurohormonal system that is overactivated in HF and contributes to its progression. These classes of drugs include ß-blockers, inhibitors of the renin-angiotensin-aldosterone system, mineralocorticoid receptor antagonists, and sodium-glucose co-transporter-2 (SGLT2) inhibitors. Unfortunately, these agents cannot be administered as frequently as needed to older patients because of poor tolerability and comorbidities. In addition, although these drugs have dramatically increased the survival expectations of patients with HF, their residual risk of rehospitalization and death at 5 years remains considerable. Vericiguat, a soluble guanylate cyclase (sGC) stimulator, was reported to exert beneficial effects in patients with worsening HF, including older subjects, reducing the rate of both hospitalizations and deaths, with limited adverse effects and drug interaction. In this narrative review, we present the current state of art on vericiguat, with a particular focus on elderly and frail patients.

Chronic Thromboembolic Pulmonary Hypertension: the therapeutic assessment.

Chronic Thromboembolic Pulmonary Hypertension (CTEPH) is a severe and complex condition that evolves from unresolved pulmonary embolism, leading to fibrotic obstruction of pulmonary arteries, pulmonary hypertension, and potential right heart failure. The cornerstone of CTEPH management lies in a multifaceted therapeutic approach tailored to individual patient profiles, reflecting the disease's heterogeneity. This review delves into the current therapeutic strategies for CTEPH, including surgical pulmonary endarterectomy (PEA), balloon pulmonary angioplasty (BPA), and targeted pharmacological treatments such as PDE5 inhibitors, endothelin receptor antagonists, sGC stimulators, and prostanoids. Lifelong anticoagulation is also highlighted as a preventive strategy against recurrent thromboembolism. Special emphasis is placed on the interdisciplinary nature of CTEPH care, necessitating collaboration among PEA surgeons, BPA interventionists, PH specialists, and thoracic radiologists to ensure comprehensive treatment planning and execution. The review underscores the importance of selecting an appropriate treatment modality based on the patient's specific disease characteristics and the evolving landscape of CTEPH treatment, aiming to improve patient outcomes through integrated care strategies.

Abnormal expression of sphingolipid-metabolizing enzymes in the heart of spontaneously hypertensive rat models.

Sphingolipids exert important roles within the cardiovascular system and related diseases. Perturbed sphingolipid metabolism was previously reported in cerebral and renal tissues of spontaneously hypertensive rats (SHR). Specific defects related to the synthesis of sphingolipids and to the metabolism of Sphingosine-1-Phospahte (S1P) were exclusively identified in the stroke-prone (SHRSP) with the respect to the stroke-resistant (SHRSR) strain. In this study, we explored any existing perturbation in either protein or gene expression of enzymes involved in the sphingolipid pathways in cardiac tissue from both SHRSP and SHRSR strains, compared to the normotensive Wistar Kyoto (WKY) strain. The two hypertensive rat models showed an overall perturbation of the expression of different enzymes involved in the sphingolipid metabolism in the heart. In particular, whereas the expression of the S1P-metabolizing-enzyme, SPHK2, was significantly reduced in both SHR strains, SGPL1 protein levels were decreased only in SHRSP. The protein levels of S1P receptors 1-3 were reduced only in the cardiac tissue of SHRSP, whereas S1PR2 levels were reduced in both SHR strains. The de novo synthesis of sphingolipids was aberrant in the two hypertensive strains. A significant reduction of mRNA expression of the Sgms1 and Smpd3 enzymes, implicated in the metabolism of sphingomyelin, was found in both hypertensive strains. Interestingly, Smpd2, devoted to sphingomyelin degradation, was reduced only in the heart of SHRSP. In conclusion, alterations in the expression of sphingolipid-metabolizing enzymes may be involved in the susceptibility to cardiac damage of hypertensive rat strains. Specific differences detected in the SHRSP, however, deserve further elucidation.