Small hairpin RNA and pharmacological targeting of neutral sphingomyelinase prevents diaphragm weakness in rats with heart failure and reduced ejection fraction.

Small hairpin RNA and pharmacological targeting of neutral sphingomyelinase prevents diaphragm weakness in rats with heart failure and reduced ejection fraction. Am J Physiol Lung Cell Mol Physiol. 2019 Jan 31;: Authors: Coblentz PD, Ahn B, Hayward LF, Yoo JK, Christou DD, Ferreira LF Abstract Heart failure with reduced ejection fraction (HFREF) increases neutral sphingomyelinase (NSMase) activity, mitochondrial reactive oxygen species emission (ROS), and causes diaphragm weakness. We tested whether a systemic pharmacologic NSMase inhibitor or short-hairpin RNA (shRNA) targeting NSMase isoform 3 (NSMase3) would prevent diaphragm abnormalities induced by HFREF caused by myocardial infarction. In the pharmacological intervention, we used intraperitoneal injection of GW4869 or vehicle. In the genetic intervention, we injected adeno-associated virus serotype 9 (AAV9) containing targeting NSMase3 or a scrambled sequence directly into the diaphragm. We also studied acid sphingomyelinase knockout mice. GW4869 prevented the increase in diaphragm ceramide content, weakness, and tachypnea caused by HFREF. For example, maximal specific forces (in N/cm2) were Vehicle: Sham 31±2 and HFREF 26±2 (P < 0.05) and GW4869: Sham 31±2 and HFREF 31±1. Respiratory rates were (in breaths/min) Vehicle: Sham 61±3 and HFREF 84±11 (P < 0.05) and GW4869: Sham 66±2 and HFREF 72±2. AAV9-NSMase3 shRNA prevented heightening of diaphragm mitochondrial RO...
Source: American Journal of Physiology. Lung Cellular and Molecular Physiology - Category: Cytology Authors: Tags: Am J Physiol Lung Cell Mol Physiol Source Type: research