Angiotensin-II receptor type Ia does not contribute to cardiac atrophy following high-thoracic spinal cord injury in mice.

NEW FINDINGS: What is the central question of this study? What is the role of the renin-angiotensin system with angiotensin II acting via its receptor AT1a in spinal cord injury-induced cardiac atrophy? What is the main finding and its importance? Knockout of AT1a did not protect mice that had undergone thoracic level 4 transection from cardiac atrophy. There were no histopathological signs but there was reduced load-dependent left ventricular function (lower stroke volume and cardiac output) with preserved ejection fraction. ABSTRACT: Spinal cord injury (SCI) leads to cardiac atrophy often accompanied by functional deficits. The renin-angiotensin system (RAS) with angiotensin II (AngII) signalling via its receptor AT1a might contribute to cardiac atrophy post-SCI. We performed spinal cord transection at thoracic level T4 (T4-Tx) or sham-operation in female wild-type mice (WT, n = 27) and mice deficient in AT1a (Agtr1a-/- , n = 27). Echocardiography (0, 7, 21 and 28 days post-SCI) and histology and gene expression analyses at 1 and 2 months post-SCI were performed. We found cardiac atrophy post-SCI: reduced heart weight, reduced estimated left ventricular mass in Agtr1a-/- , and reduced cardiomyocyte diameter in WT mice. Although, the latter as well as stroke volume (SV) and cardiac output (CO) were reduced in Agtr1a-/- mice already at baseline, cardiomyocyte diameter was even smaller in injured Agtr1a-/- mice compared to injured WT mice. SV and CO were reduced in WT mice post-SCI. Ejection fraction and fractional shortening were preserved post-SCI in both genotypes. There were no histological signs of fibrosis and pathology in the cardiac sections of either genotype post-SCI. Gene expression of Agtr1a showed a trend for up-regulation at 2 months post-SCI; angiotensinogen was up-regulated at 2 month post-SCI in both genotypes. AngII receptor type 2 (Agtr2) was up- and down-regulated at 1 and 2 months post-SCI in WT mice, respectively, and Ang-(1-7) receptor (Mas) at 1 and 2 months post-SCI. Atrogin-1/MAFbx and MuRF1, atrophy markers, were not significantly up-regulated post-SCI. Our data show that lack of AT1a does not protect from cardiac atrophy post-SCI.

Angiotensin-(1-7) Receptor Mas Deficiency Does Not Exacerbate Cardiac Atrophy Following High-Level Spinal Cord Injury in Mice.

Experimental spinal cord injury (SCI) causes a morphological and functional deterioration of the heart, in which the renin-angiotensin system (RAS) might play a role. The recently discovered non-canonical axis of RAS with angiotensin-(1-7) and its receptor Mas, which is associated with cardioprotection could be essential to prevent damage to the heart following SCI. We investigated the cardiac consequences of SCI and the role of Mas in female wild-type (WT, n = 22) and mice deficient of Mas (Mas-/- , n = 25) which underwent spinal cord transection at thoracic level T4 (T4-Tx) or sham-operation by echocardiography (0, 7, 21, and 28 days post-SCI), histology and gene expression analysis at 1 or 2 months post-SCI. We found left ventricular mass reduction with preserved ejection fraction (EF) and fractional shortening in WT as well as Mas-/- mice. Cardiac output was reduced in Mas-/- mice, whereas stroke volume (SV) was reduced in WT T4-Tx mice. Echocardiographic indices did not differ between the genotypes. Smaller heart weight (HW) and smaller cardiomyocyte diameter at 1 month post-SCI compared to sham mice was independent of genotype. The muscle-specific E3 ubiquitin ligases Atrogin-1/MAFbx and MuRF1 were upregulated or showed a trend for upregulation in WT mice at 2 months post-SCI, respectively. Angiotensinogen gene expression was upregulated at 1 month post-SCI and angiotensin II receptor type 2 downregulated at 2 month post-SCI in Mas-/- mice. Mas was downregulated post-SCI. Cardiac atrophy following SCI, not exacerbated by lack of Mas, is a physiological reaction as there were no signs of cardiac pathology and dysfunction.