Apolipoprotein A-I mimetic peptide 4F rescues pulmonary hypertension by inducing microRNA-193-3p

Pulmonary arterial hypertension is a chronic lung disease with progressive pulmonary vascular remodeling. A pathogenic role of oxidized lipids is well established in vascular diseases such as atherosclerosis. The high-density lipoprotein mimetic peptide known as 4F binds with high affinity to the oxidized lipids, reduces their levels, and thus improves vascular disease. Recently, small noncoding RNA molecules called microRNAs have emerged as potent regulatory molecules. Several microRNAs have been reported to regulate the development and progression of pulmonary hypertension (PH). In this study, we demonstrate that the plasma levels of oxidized lipids are increased in the experimental PH model. Furthermore, we show that 4F rescues advanced PH and reduces the levels of plasma oxidized lipids in PH. We also show that the microRNA-193-3p (miR193) is significantly downregulated in experimental PH and in the lung tissue and plasma in pulmonary arterial hypertension patients. A key finding is that 4F is able to restore expression of miR193 in the lungs to its levels in healthy controls via transcription factor retinoid X receptor α. Another important finding of this study is that overexpression of miR193 in the lung tissue of PH rodents is sufficient to rescue PH and inhibit proliferation of human pulmonary artery smooth muscle cells isolated from pulmonary arterial hypertension patients. MiR193 targets a number of lipoxygenases involved in the production of oxidized lipids. Our study has delineated the involvement of oxidized lipids in PH and highlights miR193 as the novel and nodal regulatory molecule by which mimetic peptide 4F entails its therapeutic effect in PH.

Sharma S, Umar S, Potus F, Iorga A, Wong G, Meriwether D, Breuils-Bonnet S, Mai D, Navab K, Ross D, Navab M, Provencher S, Fogelman AM, Bonnet S, Reddy ST, Eghbali M. Apolipoprotein A-I mimetic peptide 4F rescues pulmonary hypertension by inducing microRNA-193-3p. Circulation. 2014 Aug 26;130(9):776-85.

Spinal Neuraxial Reflex Modulation of Ventricular Arrhythmogenesis

Sudden cardiac death (SCD) due to ventricular tachyarrhythmias is the leading cause of mortality in the USA. Selective neuraxial modulation, such as thoracic epidural anesthesia and stellate ganglion blocks, provide novel therapeutic pathways to SCD intervention. However, there are major gaps in understanding neuraxial regulation of cardiac excitability- from the spinal ganglia and spinal cord to the intrinsic cardiac nervous system. The goal of our work is to determine the role of cardiac afferent neural inputs, from the heart to the spinal cord, in modulating sympathetic control of ventricular electrophysiology in normal hearts. We have shown that thoracic dorsal root cardiac afferent neural input tonically modulates efferent sympathetic control of the heart. In addition we are investigating the therapeutic benefits of thoracic epidural anesthesia in a porcine model where cardiac neural afferents are altered by acute myocardial ischemia. We have found that thoracic epidural anesthesia reduces ischemia induced cardiac excitability through neuromodulation of the dorsal (afferent) and ventral (efferent) roots at the thoracic level. Lethal ventricular arrhythmias are often associated with focal reentrant circuits in the ischemic and border zones, thus these findings provide important mechanistic evidence supporting treatment of ventricular arrhythmias using thoracic epidural anesthesia.

  1. Howard-Quijano K, Yamakawa K, Zhou W, Shivkumar K, Mahajan A. Cardiospinal Reflex Modulation of Ventricular Arrhythmogenesis.
  2. Howard-Quijano K, Yamakawa K, Zhou W, Takamiya T, Zhou W, Ardell J, Shivkumar K, Mahajan A. Thoracic Epidural Anesthesia Suppresses Cardiac Excitability Induced by Acute Myocardial Ischemia
  3. Yamakawa, K., Howard Quijano, K., Zhou, W., Rajendran, P. S., Yagishita, D., Vaseghi, M., Mahajan, A. Central vs peripheral neuraxial sympathetic control of porcine ventricular electrophysiology. Am J Physiol Regul Integr Comp Physiol. 2015 Dec 9.

Use of advanced speckle tracking strain echocardiography imaging to define cardiac effects of anesthesia and surgical interventions on myocardial function

Advances in technology now allow direct measurement of myocardial deformation through speckle tracking strain imaging. Strain measurements can be made from either 2-dimensional or 3-dimensional echocardiography images obtained from transthoracic and transesophageal echocardiography. We have applied this advance echo technology to investigate the changes in left atrial mechanics associated with general anesthesia and positive pressure ventilation as well as changes in myocardial function associated with cardiac surgery. Using 3D transthoracic strain imaging pre- and post-cardiac surgery we investigated global and regional changes in myocardial function. Importantly we found that there as a significant reduction in ventricular myocardial function which was an independent predictor of worsening acute postoperative outcomes and 1-yr event free survival. These findings can help direct changes in perioperative care to optimize both acute and long-term postoperative outcomes following cardiac surgery.

  1. Howard-Quijano K, Salem A, Mazor E, Barkulis C, Scovotti J, Ho, JK, Mahajan A. Preoperative Three-Dimensional Strain Imaging is an Independent Risk Factor for Worsening Outcomes After Coronary Artery Bypass Surgery
  2. Howard Quijano, K, Anderson Dam, J, McCabe, M, Mahajan A. Speckle-Tracking Strain Imaging Identifies Alterations in Left Atrial Mechanics With General Anesthesia and Positive-Pressure Ventilation. J Cardiothorac Vasc Anesth. 2015 Aug;29(4), 845-51.

Involvement of Opioid Receptors in the Lipid Rescue of Bupivacaine-Induced Cardiotoxicity

Lipid emulsion (LE) has been successfully used for resuscitation of local anesthetic cardiotoxicity caused by Bupivacaine overdose. Opioid receptors have been shown to play a key role in cardio protection. In this study we explored whether this rescue action of LE is mediated through opioid receptors. Through a series of carefully performed experiments using non-selective opioid receptor antagonist such as naloxone and naloxone methiodide as well as highly selective opioid receptor antagonists for subtype κ, δ, and µ, our data highlighted the involvement of peripheral δ- and κ-opioid receptors in the rescue action of LE.

Partownavid P, Sharma S, Li J, Umar S, Rahman S, Eghbali M. Anesth Analg. 2015 Aug;121(2):340-7.

Recovery of consciousness is mediated by a network of discrete metastable activity states.

General anesthesia, by causing reversible unconsciousness, provides a unique model system for the study of how neuronal activity changes during recovery of consciousness. Using traditional electrophysiology, we tracked the evolution over time of the power spectrum in multiple brain areas simultaneously as rats recovered consciousness from slowly decreasing levels of isoflurane anesthesia. We found that brain state tends to jump spontaneously between several electrophysiologic patterns during anesthesia, identified by the presence of clusters in principal component space. Because these clusters represent specific patterns of power in ongoing activity of cortex and thalamus that are relatively stabilized, we call them metastable activity states. Of particular interest, transitions between these metastable activity states were not random or uniform, with particular clusters forming hubs in the network of observed brain state patterns, such that transition from “deep” activity patterns dominated by slow oscillations to “lighter” activity patterns with delta or theta dominant oscillations always occurred by transitioning through the hub states, suggesting that brain activity follows something akin to a “boot sequence” during recovery from anesthesia, where the establishment of certain brain activity patterns appears to be necessary for the transition to activity patterns compatible with recovery of consciousness.

Hudson AE, Calderon DP, Pfaff DW, Proekt A. Recovery of consciousness is mediated by a network of discrete metastable activity states. Proc Natl Acad Sci U S A. 2014 Jun 24;111(25):9283-8.