Conflicting results have been reported for the roles of cGMP and cGMP-dependent protein kinase I (cGKI) in various pathological conditions leading to cardiac hypertrophy and fibrosis. A cardioprotective effect of cGMP/cGKI has been reported in whole animals and isolated cardiomyocytes, but recent evidence from a mouse model expressing cGKIβ only in smooth muscle (βRM) but not in cardiomyocytes, endothelial cells, or fibroblasts has forced a reevaluation of the requirement for cGKI activity in the cardiomyocyte antihypertrophic effects of cGMP. In particular, βRM mice developed the same hypertrophy as WT controls when subjected to thoracic aortic constriction or isoproterenol infusion. Here, we challenged βRM and WT (Ctr) littermate control mice with angiotensin II (AII) infusion (7 d; 2 mg·kg −1 ·d −1 ) to induce hypertrophy. Both genotypes developed cardiac hypertrophy, which was more pronounced in Ctr animals. Cardiomyocyte size and interstitial fibrosis were increased equally in both genotypes. Addition of sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, in the drinking water had a small effect in reducing myocyte hypertrophy in WT mice and no effect in βRM mice. However, sildenafil substantially blocked the increase in collagen I, fibronectin 1, TGFβ, and CTGF mRNA in Ctr but not in βRM hearts. These data indicate that, for the initial phase of AII-induced cardiac hypertrophy, lack of cardiomyocyte cGKI activity does not worsen hypertrophic growth. However, expression of cGKI in one or more cell types other than smooth muscle is necessary to allow the antifibrotic effect of sildenafil.PKGI | PDE | cardiac failure | hypertension | NO/cyclic GMP system

Background: ␤-Adrenergic receptors stimulate cardiac I Ca via PKA-dependent phosphorylation. Results: Deletion of the C-terminal phosphorylation sites in the ␤ 2 gene did not affect isoproterenol-stimulated I Ca . Conclusion: Phosphorylation of the C terminus of the ␤ 2 subunit in vivo does not contribute to ␤-adrenergic regulation of I Ca . Significance: The PKA-dependent regulation of I Ca does not require the C terminus of the ␤ 2 subunit.

The cardiac Ca V 1.2 calcium channel, a dihydropyridine-sensitive L-type channel, is widely expressed and is of functional importance for neurons, the cardiac myocytes (CMs), 2 and vascular and intestinal smooth muscle (1). Global and heart specific deletion of the Ca V 1.2 gene is embryonically lethal (2). Smooth muscle-specific deletion of the Ca V 1.2 channel leads to defects in blood pressure regulation (3), intestinal dysfunction (4), and death (5). In contrast to the cardiovascular system, deletion of the Ca V 1.2 channel in the CNS does not affect survival. However, its specific deletion affects learning processes in the hippocampus and in the lateral amygdala (6, 7).Voltage-dependent opening of the Ca V 1.2 channel facilitates greatly Ca 2ϩ entry into CMs and triggers thereby opening of ryanodine receptors to initiate muscle contraction. Two mechanisms allow closing of the channel, namely a Ca 2ϩ -and a voltage-dependent process. Ca 2ϩ -dependent inactivation is mediated by the carboxyl terminus of the channel (CCt). There is excellent evidence that modifications at the CCt affect significantly the inactivation of the channel (8 -15). Cardiac Ca V 1.2 channels are modulated by CaM and CaM kinase II (CaM-KII). Voltage-dependent facilitation of the channel requires in vitro and in vivo the CaM-KII dependent phosphorylation of Ser-1512 and Ser-1570 (16, 17). In addition, binding of CaM to the IQ motif located in the CCt is essential for Ca 2ϩ -dependent inhibition and facilitation of the channel (8,10,18,19).The distal CCt of the Ca V 1.2 channel (amino acids 1642-2143) has been reported to translocate to the nucleus and to modulate the transcription of several genes (20). Cleavage of the channel at residue 1623 does not result in a functional channel protein (21). However, proteolytic cleavage of the channel at residue 1821 (22) yields a functional channel and an inhibitory molecule of 35 kDa (23). At present it is not clear, if the proteolytic processing of the C terminus of Ca V 1.2 is a regulated or tonic event and which processes control translocation of CCt to the nucleus. Nuclear location increased with low cytosolic [Ca 2ϩ ] and decreased with increasing cytosolic [Ca 2ϩ ], i.e. with activation of the truncated Ca V 1.2 channel (20). In neurons, the CCt regulates the expression of a number of genes (20), whereas in CMs, the truncated CCt (amino acids 1906 -2171) caused an 80% decrease of the Ca V 1.2 promoter activity (23). Furthermore, proteolysis of the Ca V 1.2 protein appears to be important to observe cAMP kinase-dependent regulation of the channel (15). In tsA-201 cells, coexpression of a rabbit Ca V 1.2a-1800stop channel together with the proteolytically derived CCt of the Ca V 1.2 was essential to observe a cAMP kinase-induced positive inotropic effect (15). On the other hand, a cAMP kinase-dependent regulation of the Ca V 1.2a channel was reported, when a Ca V 1.2-1905stop construct was expressed in HEK293 cells together with the Ca V ␤2 subunit (24) but not when co-expressed in guinea ...

No abstract

The heart muscle responds to physiological needs with a short-term modulation of cardiac contractility. This process is determined mainly by properties of the cardiac L-type Ca