Musashi-2 causes cardiac hypertrophy and heart failure by inducing mitochondrial dysfunction through destabilizing Cluh and Smyd1 mRNA.

Regulation of RNA stability and translation by RNA-binding proteins (RBPs) is a crucial process altering gene expression. Musashi family of RBPs comprising Msi1 and Msi2 is known to control RNA stability and translation. However, despite the presence of MSI2 in the heart, its function remains largely unknown. Here, we aim to explore the cardiac functions of MSI2. We confirmed the presence of MSI2 in the adult mouse, rat heart, and neonatal rat cardiomyocytes. Furthermore, Msi2 was significantly enriched in the heart cardiomyocyte fraction. Next, using RNA-seq data and isoform-specific PCR primers, we identified Msi2 isoforms 1, 4, and 5, and two novel putative isoforms labeled as Msi2 6 and 7 to be expressed in the heart. Overexpression of Msi2 isoforms led to cardiac hypertrophy in cultured cardiomyocytes. Additionally, Msi2 exhibited a significant increase in a pressure-overload model of cardiac hypertrophy. We selected isoforms 4 and 7 to validate the hypertrophic effects due to their unique alternative splicing patterns. AAV9-mediated overexpression of Msi2 isoforms 4 and 7 in murine hearts led to cardiac hypertrophy, dilation, heart failure, and eventually early death, confirming a pathological function for Msi2. Using global proteomics, gene ontology, transmission electron microscopy, seahorse, and transmembrane potential measurement assays, increased MSI2 was found to cause mitochondrial dysfunction in the heart. Mechanistically, we identified Cluh and Smyd1 as direct downstream targets of Msi2. Overexpression of Cluh and Smyd1 inhibited Msi2-induced cardiac malfunction and mitochondrial dysfunction. Collectively, we show that Msi2 induces hypertrophy, mitochondrial dysfunction, and heart failure.

Pyrroloquinoline quinone (PQQ) improves pulmonary hypertension by regulating mitochondrial and metabolic functions.

Excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) and endothelial cells (PAECs), inflammation, as well as mitochondrial and metabolic dysregulation, contributes to the development of pulmonary hypertension (PH). Pyrroloquinoline quinone (PQQ), a potent natural antioxidant with anti-diabetic, neuroprotective, and cardioprotective properties, is known to promote mitochondrial biogenesis. However, its effect on cellular proliferation, apoptosis resistance, mitochondrial and metabolic alterations associated with PH remains unexplored. The current study was designed to investigate the effect of PQQ in the treatment of PH. Human pulmonary artery smooth muscle cells (HPASMCs), endothelial cells (PAECs), and primary cultured cardiomyocytes were subjected to hypoxia to induce PH-like phenotype. Furthermore, Sprague Dawley (SD) rats injected with monocrotaline (MCT) (60 mg/kg, SC, once) progressively developed pulmonary hypertension. PQQ treatment (2 mg/kg, PO, for 35 days) attenuated cellular proliferation and promoted apoptosis via a mitochondrial-dependent pathway. Furthermore, PQQ treatment in HPASMCs prevented mitochondrial and metabolic dysfunctions, improved mitochondrial bioenergetics while preserving respiratory complexes, and reduced insulin resistance. In addition, PQQ treatment (preventive and curative) significantly attenuated the increase in right ventricle pressure and hypertrophy as well as reduced endothelial dysfunction and pulmonary artery remodeling in MCT-treated rats. PQQ also prevented cardiac fibrosis and improved cardiac functions as well as reduced inflammation in MCT-treated rats. Altogether, the above findings demonstrate that PQQ can attenuate mitochondrial as well as metabolic abnormalities in PASMCs and also prevent the development of PH in MCT treated rats; hence PQQ may act as a potential therapeutic agent for the treatment of PH.

Ethanolic extract of Cissus quadrangularis improves vasoreactivity by modulation of eNOS expression and oxidative stress in spontaneously hypertensive rats.

BACKGROUND: Endothelial dysfunction is related to the reduced bioavailability of nitric oxide (NO) and plays a significant role in developing hypertension. The intake of a diet rich in antioxidants decreases the threat of hypertension. Cissus quadrangularis possesses antioxidant, anti-inflammatory, and hypocholesterolemic activities. However, to date, no studies have been performed to explore this plant's antihypertensive and vasorelaxant activity. Herein, we investigated the chronic effect of C. quadrangularis on blood pressure as well as vascular function in hypertensive rats. METHODS: Male spontaneously hypertensive rats (SHR) were randomly divided into two groups. Normotensive Wistar rats were taken as the control group. The treatment was done using ethanolic extract of C. quadrangularis (EECQ) at a dose of 200 mg/kg. RESULTS: The administration of EECQ for six weeks reduced the systolic blood pressure, mean arterial blood pressure, and heart rate. It also alleviated the cardiac and renal hypertrophy indices. Supplementation of EECQ improved the endothelium-dependent aortic vasodilation induced by acetylcholine. It restored the NO level and endothelial NO synthase expression in the aorta. Subsequently, the extract alleviates the oxidative stress and inflammatory markers in SHR rats. CONCLUSION: Thus, in the present study, the chronic treatment of EECQ to genetically hypertensive rats improved endothelium-dependent relaxation in addition to its antihypertensive effect by eNOS activation and inhibition of ROS production, inflammation.

Involvement of mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2) in endothelial dysfunction associated with pulmonary hypertension.

AIMS: Increased proliferation, inflammation, and endothelial microparticle (EMP) generation in the pulmonary vasculature lead to endothelial dysfunction in pulmonary hypertension (PH). Interestingly, MK2, a downstream of p38MAPK, is a central regulator of inflammation, proliferation, and EMP generation in cardiovascular diseases. However, the role of MK2 in pulmonary endothelial dysfunction remains unexplored. MAIN METHODS: The Human Pulmonary Artery Endothelial cells (HPAECs) were exposed to hypoxia (1% O2) for 72 h, and MK2 inhibition was achieved by siRNA treatment. Western blotting, qualitative RT-PCR, immunocytochemistry, flow cytometry and enzyme-linked immunoassays were conducted to study pathological alterations and molecular mechanisms. Neoangiogenesis was studied using cell migration and tubule formation assays. For in vivo study, Male Sprague Dawley rats and MK2 knock-out mice with littermate control were treated with monocrotaline (MCT) 60 mg/kg and 600 mg/kg, respectively (s.c. once in rat and weekly in mice) to induce PH. MMI-0100 (40 µg/kg, i.p. daily for 35 days), was administered in rats to inhibit MK2. KEY FINDINGS: MK2 inhibition significantly decreased inflammation, cell proliferation, apoptosis resistance, and improved mitochondrial functions in hypoxic HPAECs. Hypoxia promoted cell migration, VEGF expression, and angiogenesis in HPAECs, which were also reversed by MK2 siRNA. MK2 inhibition decreased EMP generation and increased the expression of p-eNOS in hypoxic HPAECs, a marker of endothelial function. Furthermore, MK2 deficiency and inhibition both reduced the EMP generation in mice and rats, respectively. SIGNIFICANCE: These findings proved that MK2 is involved in endothelial dysfunction, and its inhibition may be beneficial for endothelial function in PH.