Computed tomography reveals hip dysplasia in the extinct Pleistocene saber-tooth cat Smilodon

Reconstructing the behavior of extinct species is challenging, particularly for those with no living analogues. However, damage preserved as paleopathologies on bone can record how an animal moved in life, potentially reflecting behavioral patterns. Here, we assess hypothesized etiologies of pathology in a pelvis and associated right femur of a Smilodon fatalis saber-toothed cat, one of the best-studied species from the Pleistocene-age Rancho La Brea asphalt seeps, California, USA, using visualization by computed tomography (CT). The pelvis exhibits massive destruction of the right hip socket that was interpreted, for nearly a century, to have developed from trauma and infection. CT imaging reveals instead that the pathological distortions characterize chronic remodeling that began at birth and led to degeneration of the joint over the animal’s life. These results suggest that this individual suffered from hip dysplasia, a congenital condition common in domestic dogs and cats. This individual reached adulthood but could not have hunted properly nor defended territory on its own, likely relying on a social group for feeding and protection. While extant social felids are rare, these fossils and others with similar pathologies are consistent with a spectrum of social strategies in Smilodon supported by a predominance of previous studies.

MIR1183 as a new tissue biomarker with triggered acute response and upregulation in chronic atrial and ventricular remodeling

Background and purpose Cardiac remodeling can be caused by a variety of insults linked to either stretch or tachycardia as a triggering mechanism. We aimed to investigate similarities and differences of the transcriptomic profiles in response to either acute stretch or tachycardia in isolated human atrial myocardium. In addition, we tested the highest acutely regulated target for its chronic regulation in human tissue with atrial or ventricular cardiac remodeling. Methods For acute trigger testing we applied either stretch (high pre- and afterload) or sustained tachycardia (2.5 Hz) for 6 hours in isolated atrial human trabeculae from cardiac surgery patients (all in sinus rhythm, SR). We performed gene expression profiling by RNA microarrays (n=5 per group) as a remodeling readout. For chronic regulation we performed qPCR of selected genes of interest in right atrial appendage tissue obtained from cardiac surgery patients with persistent atrial fibrillation compared to control patients with SR (n=6 per group), and also in ventricular tissue samples from failing hearts (from transplanted dilative cardiomyopathy patients) or non-failing control hearts (from multi-organ donors denied for transplantation), n=6 per group. Results The expression patterns of stretch and tachycardia were largely independent with 1305 transcripts regulated solely by stretch and 1837 transcripts by tachycardia with p<0.05. In contrast, the fraction of commonly regulated genes was small (65 transcripts with p<0.05). However, this fraction contained the strongest upregulated transcript, the microRNA precursor gene MIR1183, which was similarly upregulated by both triggers (4.1fold in stretch and 2.7fold in tachycardia, both p<0.05). MIR1183 also showed upregulation in two important chronic remodeling settings: In atrial samples with persistent atrial fibrillation in comparison to sinus rhythm, it was 2.8fold upregulated, and in ventricular samples from dilative cardiomyopathy hearts it was 1.6fold upregulated (p<0.05 for both). A functional role of MIR1183 in remodeling was also suggested by significant downregulation of its predicted downstream target genes ADAM20 and PLA2G7. Our ongoing research aims to confirm upregulation also in the circulating expression levels of the mature form of MIR1183 in human plasma samples in a cohort of atrial fibrillation patients with diseased atria, these findings will also be presented at scientific sessions. Conclusion Stretch and tachycardia show distinct transcriptomic signatures in human atrial trabeculae but share the strongest upregulated gene MIR1183 and consistent regulation of its downstream targets. This is present in an acute as well as chronic remodeling setting. Expression levels of MIR1183 might serve as a biomarker for atrial remodeling and to some extend ventricular remodeling and have potential functional significance in cardiac disease. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Medical University of Graz

CRABP1 protects the heart from isoproterenol-induced acute and chronic remodeling

Excessive and/or persistent activation of calcium-calmodulin protein kinase II (CaMKII) is detrimental in acute and chronic cardiac injury. However, intrinsic regulators of CaMKII activity are poorly understood. We find that cellular retinoic acid-binding protein 1 (CRABP1) directly interacts with CaMKII and uncover a functional role for CRABP1 in regulating CaMKII activation. We generated Crabp1-null mice (CKO) in C57BL/6J background for pathophysiological studies. CKO mice develop hypertrophy as adults, exhibiting significant left ventricular dilation with reduced ejection fraction at the baseline cardiac function. Interestingly, CKO mice have elevated basal CaMKII phosphorylation at T287, and phosphorylation on its substrate phospholamban (PLN) at T17. Acute isoproterenol (ISO) challenge (80 mg/kg two doses in 1 day) causes more severe apoptosis and necrosis in CKO hearts, and treatment with a CaMKII inhibitor KN-93 protects CKO mice from this injury. Chronic (30 mg/kg/day) ISO challenge also significantly increases hypertrophy and fibrosis in CKO mice as compared to WT. In wild-type mice, CRABP1 expression is increased in early stages of ISO challenge and eventually reduces to the basal level. Mechanistically, CRABP1 directly inhibits CaMKII by competing with calmodulin (CaM) for CaMKII interaction. This study demonstrates increased susceptibility of CKO mice to ISO-induced acute and chronic cardiac injury due to, at least in part, elevated CaMKII activity. Deleting Crabp1 results in reduced baseline cardiac function and aggravated damage challenged with acute and persistent β-adrenergic stimulation. This is the first report of a physiological role of CRABP1 as an endogenous regulator of CaMKII, which protects the heart from ISO-induced damage.