Activation of the Amino Acid Response Pathway Blunts the Effects of Cardiac Stress.

BACKGROUND: The amino acid response (AAR) is an evolutionarily conserved protective mechanism activated by amino acid deficiency through a key kinase, general control nonderepressible 2. In addition to mobilizing amino acids, the AAR broadly affects gene and protein expression in a variety of pathways and elicits antifibrotic, autophagic, and anti-inflammatory activities. However, little is known regarding its role in cardiac stress. Our aim was to investigate the effects of halofuginone, a prolyl-tRNA synthetase inhibitor, on the AAR pathway in cardiac fibroblasts, cardiomyocytes, and in mouse models of cardiac stress and failure. METHODS AND RESULTS: Consistent with its ability to inhibit prolyl-tRNA synthetase, halofuginone elicited a general control nonderepressible 2-dependent activation of the AAR pathway in cardiac fibroblasts as evidenced by activation of known AAR target genes, broad regulation of the transcriptome and proteome, and reversal by l-proline supplementation. Halofuginone was examined in 3 mouse models of cardiac stress: angiotensin II/phenylephrine, transverse aortic constriction, and acute ischemia reperfusion injury. It activated the AAR pathway in the heart, improved survival, pulmonary congestion, left ventricle remodeling/fibrosis, and left ventricular function, and rescued ischemic myocardium. In human cardiac fibroblasts, halofuginone profoundly reduced collagen deposition in a general control nonderepressible 2-dependent manner and suppressed the extracellular matrix proteome. In human induced pluripotent stem cell-derived cardiomyocytes, halofuginone blocked gene expression associated with endothelin-1-mediated activation of pathologic hypertrophy and restored autophagy in a general control nonderepressible 2/eIF2α-dependent manner. CONCLUSIONS: Halofuginone activated the AAR pathway in the heart and attenuated the structural and functional effects of cardiac stress.

Pilot study on cardiac troponin I levels in dogs with pericardial effusion.

OBJECTIVES: The aim of this pilot study was to assess cardiac troponin I (cTnI) levels in pericardial effusion (PE) and plasma from dogs with PE. BACKGROUND: A reliable marker for detecting the etiology of PE in dogs remains undetermined. cTnI is becoming the gold standard marker for detecting myocardial damage in humans. ANIMALS, MATERIALS AND METHODS: Twenty-five dogs with PE (21 and 4 secondary to neoplasia and non-neoplasia causes, respectively) and 37 control dogs were studied. RESULTS: The median cTnI plasma level from 37 normal dogs versus 15 (out of 25) with PE was 0.03ng/mL and 0.19ng/mL, respectively (p<0.0001). The level of cTnI in PE versus plasma showed a significant correlation (p<0.01) with a Spearman r coefficient of 0.7603. No significant difference could be found upon comparison of dogs with only right atrial tumors (n=14) versus other types of neoplasia (n=7), nor between the group with right atrial tumors (n=14) versus all other cases including neoplasia as well as non-neoplasia (n=11). The median cTnI level in PE from dogs with neoplasia and non-neoplasia was not significantly different. CONCLUSIONS: cTnI did rise significantly in both PE and plasma in dogs with PE, but cTnI levels did not help differentiate between etiologies according to this study. One of the study groups is too small to allow final conclusions, and thus further investigation is warranted.