Role of the Neurogenic Signaling on Cardiac miR‐18‐5p/HIF‐1α Axis to Enhance Mitochondrial Abnormality in Neurogenic Hypertension
Authors: Nandi Shyam S. , Haibara Andrea S , Mahata Sushil K , Sharma Neeru M , Katsurada Kenichi , Patel Kaushik P 
Published: June 2021

Hypertension increases the risk of heart disease. One hallmark feature of the disease is an abnormal mitochondrial (mt) function in the heart, where HIF‐1α (hypoxia‐inducible factor‐1α, a mitochondrial suppressor) protein level is increased and the level of miR‐18‐5p (an anti‐hypertrophy and anti‐fibrosis microRNA) is decreased. In the present study, we evaluated pathological cardiac remodeling and determined whether decreased cardiac miR‐18‐5p contributes to the HIF‐1α‐induced mt‐abnormality in the hearts of rats with neurogenic hypertension. Sprague‐Dawley rats (250–300 g) were subjected to ICV infusion of Angiotensin II (Ang II at 20 ng/min) or 0.9% sterile saline (0.5μl/h) through osmotic mini‐pumps for 14 days. Central infusion of Ang II increased sympathoexcitation which leads to hypertension. Cardiac level of miR‐18‐5p, HIF‐1α, and mitochondrial parameters were measured by qPCR, Western blot, immunohistochemistry and electron microscopy (EM). Differentiated H9C2 rat cardiomyocytes were treated in vitro with norepinephrine (NE) to mimic the hyper‐sympathetic phenotype of neurogenic hypertension. In addition, miR‐18‐5p mimic or inhibitor oligomers were used for inducing miR‐18‐5p gain or loss of function. Our results showed that central Ang II infusion for 14 days induce hypertensive cardiac remodeling compared to saline infusion (HW/BW ratio: 3.1±0.06 vs. 3.4±0.09; hypertrophy: 35.1±4.04 vs. 45.9±2.91; fibrosis: 2.9±0.44 vs. 5.0 ± 0.6). The Ang II infusion group showed decreased miR‐18‐5p level (1.19±0.09 vs. 0.6±0.06) and increased HIF‐1α protein level (1.1±0.14 vs. 2.09±0.2) in the heart. The mtDNA copy number showed reduced mitochondrial biogenesis (1.17±0.1 vs. 0.75±0.04) and EM showed impaired mt‐cristae structures in the heart of Ang II‐infused compared to saline‐infused rats, suggesting mt‐abnormality in the hearts of rats with neurogenic hypertension. NE treatment in H9C2 cardiomyocytes showed decreased miR‐18‐5p level (1.03±0.04 vs. 0.70±0.10), increased HIF‐1α protein level (0.84±0.18 vs. 1.37±0.05) and decreased mtDNA copy number (1.05±0.11 vs. 0.54±0.10), indicating decreased mt‐dynamics. Further, miR‐18‐5p inhibitor increased mt‐fragmentation, which is mitigated by miR‐18‐5p mimic in H9C2 cardiomyocytes (mt‐length; anti‐miR: 14.9±1.21 vs. miR: 39.8±3.5). MiR‐18‐5p mimic decreased HIF‐1α protein level in H9C2 cardiomyocytes compared to scramble (0.76±0.07 vs. 0.53±0.03). Our in‐silico analysis confirmed that miR‐18‐5p targets HIF‐1α 3/UTR (ACACUGG, position 177‐183), which is broadly conserved among species. Taken together, our studies suggest that increased central activation of the sympathetic nervous system in neurogenic hypertension contribute to the decreased cardiac levels of miR‐18‐5p for HIF‐1α stabilization, which appears to be subsequently involved in mitochondrial suppression and pathological cardiac remodeling.Support or Funding InformationHL62222 and DK114663This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.