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Treatment of hypertension-mediated cardiac damage with left ventricular (LV) hypertrophy (LVH) and heart failure remains challenging. To identify novel targets, we performed comparative transcriptome analysis between genetic models derived from stroke-prone spontaneously hypertensive rats (SHRSP). Here, we identified carboxypeptidase X 2 (Cpxm2) as a genetic locus affecting LV mass. Analysis of isolated rat cardiomyocytes and cardiofibroblasts indicated Cpxm2 expression and intrinsic upregulation in genetic hypertension. Immunostaining indicated that CPXM2 associates with the t-tubule network of cardiomyocytes. The functional role of Cpxm2 was further investigated in Cpxm2-deficient (KO) and wild-type (WT) mice exposed to deoxycorticosterone acetate (DOCA). WT and KO animals developed severe and similar systolic hypertension in response to DOCA. WT mice developed severe LV damage, including increases in LV masses and diameters, impairment of LV systolic and diastolic function and reduced ejection fraction. These changes were significantly ameliorated or even normalized (i.e., ejection fraction) in KO-DOCA animals. LV transcriptome analysis showed a molecular cardiac hypertrophy/remodeling signature in WT but not KO mice with significant upregulation of 1234 transcripts, including Cpxm2, in response to DOCA. Analysis of endomyocardial biopsies from patients with cardiac hypertrophy indicated significant upregulation of CPXM2 expression. These data support further translational investigation of CPXM2., Differential increased cardiac expression of Cpxm2 was assigned to cardiac hypertrophy in SHRSP rats. Cpxm2 knock-out (KO) in mice reduced cardiac hypertrophy and remodeling in DOCA salt hypertension

Background and Purpose— Chronic stress is associated with increased stroke risk. However, the underlying pathophysiological mechanisms are poorly understood. We examined the effects of chronic stress on endothelial function and ischemic brain injury in a mouse model. Methods— 129/SV mice were treated with glucocorticoid receptor antagonist mifepristone (25 mg kg −1 /d) or vehicle and exposed to 28 days of chronic stress consisting of exposure to rat, restraint stress, and tail suspension. Heart rate and blood pressure were continuously recorded by telemetry. Endothelial nitric oxide synthase mRNA and protein expression as well as superoxide production and lipid hydroperoxides were quantified. Endothelium-dependent vasorelaxation was measured in aortic rings. Ischemic lesion volume was quantified after 30 minutes filamentous middle cerebral artery occlusion and 72 hours reperfusion. Results— Chronic stress caused a significant increase in heart rate, impaired endothelium-dependent vasorelaxation, increased superoxide production, and reduced aortic and brain endothelial nitric oxide synthase levels. Animals exposed to chronic stress showed major increases in ischemic lesion size. These deleterious effects of stress were completely reversed by treatment with mifepristone. Conclusions— Chronic stress increases stroke vulnerability likely through endothelial dysfunction, which can be reversed by a glucocorticoid receptor antagonist.

Leptin receptor-deficient db/db mice develop human type 2 diabetes mellitus, hypertension, and obesity with disrupted circadian blood pressure (BP) rhythm. Whether leptin is the sole mechanism mediating autonomic imbalance and hypertension is unclear. To explore this notion further, we measured BP by radiotelemetry combined with fast Fourier transformation and assessed autonomic function pharmacologically before and after renin-angiotensin system blockade with enalapril. the resting period BP (117 +/- 3 versus 108 +/- 1.0 mm Hg) and heart rate (HR; 488 +/- 12 versus 436 +/- 8 bpm) were higher in db/db mice compared with db/+ mice. BP and HR amplitudes were lower in db/db mice compared with db/+ mice. BP response to trimetaphan (-43 +/- 5 versus -27 +/- 3 mm Hg) and HR response to metoprolol (-59 +/- 12 versus -5 +/- 4 bpm) were greater in db/db mice than in db/+ mice. the HR response to atropine was blunted in db/db mice (59 +/- 17 versus 144 +/- 24 bpm), as were baroreflex sensitivity and HR variability. Enalapril improved autonomic regulation in db/db mice. Stimulation of central alpha-2 adrenoreceptors enhanced both parasympathetic HR control and baroreflex sensitivity in db/db mice. We suggest that functional, rather than structural, alpha-2 adrenoceptor changes and the renin-angiotensin system are involved in the increased sympathetic and decreased parasympathetic tones in db/db mice. Our data suggest that db/db mice exhibit features found in humans with type 2 diabetic autonomic neuropathy and could serve as a model for this complication. (Hypertension. 2009; 53[part 2]: 387-392.) Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany Hannover Med Sch, Inst Clin Pharmacol, D-3000 Hannover, Germany Universidade Federal de São Paulo, Dept Biophys, Escola Paulista Med, São Paulo, Brazil Vanderbilt Univ, Sch Med, Dept Med, Auton Dysfunct Serv,Div Clin Pharmacol, Nashville, TN 37212 USA HELIOS Klin, Franz Volhard Clin, Fac Med Charite, Berlin, Germany Universidade Federal de São Paulo, Dept Biophys, Escola Paulista Med, São Paulo, Brazil Web of Science

To study the mechanisms by which missense mutations in α-tropomyosin cause familial hypertrophic cardiomyopathy, we generated transgenic rats overexpressing α-tropomyosin with one of two disease-causing mutations, Asp175Asn or Glu180Gly, and analyzed phenotypic changes at molecular, morphological, and physiological levels. The transgenic proteins were stably integrated into the sarcomere, as shown by immunohistochemistry using a human-specific anti-α-tropomyosin antibody, ARG1. In transgenic rats with either α-tropomyosin mutation, molecular markers of cardiac hypertrophy were induced. Ca2+sensitivity of cardiac skinned-fiber preparations from animals with mutation Asp175Asn, but not Glu180Gly, was decreased. Furthermore, elevated frequency and amplitude of spontaneous Ca2+waves were detected only in cardiomyocytes from animals with mutation Asp175Asn, suggesting an increase in intracellular Ca2+concentration compensating for the reduced Ca2+sensitivity of isometric force generation. Accordingly, in Langendorff-perfused heart preparations, myocardial contraction and relaxation were accelerated in animals with mutation Asp175Asn. The results allow us to propose a hypothesis of the pathogenetic changes caused by α-tropomyosin mutation Asp175Asn in familial hypertrophic cardiomyopathy on the basis of changes in Ca2+handling as a sensitive mechanism to compensate for alterations in sarcomeric structure.