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Lack of S100A1 in mice confers a gender-dependent hypertensive phenotype and increased mortality after myocardial infarction

Divisions of ¹Cardiology and ²Cardiac Surgery, Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada

Submitted 28 January 2008 ; accepted in final form 9 March 2009

S100A1 is a small Ca²⁺-binding protein expressed in the myocardium and blood vessels that is downregulated in the diseased heart and plays a role in the regulation of cardiac muscle Ca²⁺ homeostasis and contractility. To understand its physiological role under basal conditions and after myocardial infarction (MI), we used a mouse strain with targeted deletion of the S100A1 gene [S100A1 knockout (KO) mice]. We compared 49 wild-type (WT) and 56 S100A1 KO mice (6–8 wk old) over 28 days after MI with sham-operated controls. We also examined the effect of S100A1 deficiency on vascular function of isolated blood vessels. S100A1 KO mice demonstrated worse survival compared with WT mice (21% vs. 69%, respectively, P < 0.001). Hemodynamic evaluation revealed a higher mean arterial pressure (MAP) in sham-operated KO animals compared with WT animals (99 ± 4 vs. 77 ± 3 mmHg, respectively, P < 0.001) that persisted in both groups after MI (86 ± 2 vs. 66 ± 4 mmHg, respectively, P < 0.001). Sham-operated male S100A1 KO mice had higher MAP than female KO mice (122 ± 5 vs. 93 ± 3 mmHg, respectively P < 0.05) and reduced survival after MI (4% vs. 27%, respectively, P < 0.05). In isolated aortas and mesenteric arteries, ACh-evoked vasodilatation in KO mice was significantly reduced compared with WT mice (P < 0.05). Nitric oxide production was reduced in endothelial cells isolated from KO mice. Thus, absence of S100A1 results in acute functional impairment and high mortality after MI associated with a gender-specific hypertensive phenotype. S100A1 appears to play a role in the endothelium-dependent regulation of blood pressure.

Ca²⁺-binding protein; vascular tone; heart failure; hypertrophy; knockout

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