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Molecular Mechanisms in Heart Failure

Focus on Cardiac Hypertrophy, Inflammation, Angiogenesis, and Apoptosis

Departments of Cardiology and Angiology, Hannover Medical School, Hannover, Germany

View larger version (38K): [in this window] [in a new window] [Download PPT slide]   Figure 1 Statin therapy may represent a potentially novel treatment strategy for preventing cardiac hypertrophy and for improving myocardial vascularization. Statins may exert beneficial effects in heart failure independent of cholesterol lowering by prevention of isoprenylation of small g proteins, such as Rac-1 or Rho-A, which have been shown to be critically involved in the activation of the oxidant enzyme NAD(P)H oxidase and the regulation of endothelial nitric oxide (NO) synthase expression. Prevention of NAD(P)H oxidase activation and an increased endothelial NO synthase-dependent NO availability may reduce cardiomyocyte hypertrophy and improve vascular (i.e., endothelial) function.

View larger version (44K): [in this window] [in a new window] [Download PPT slide]   Figure 2 Comparison of the interleukin (IL)-6–glycoprotein 130 (gp130)–Janus kinase (JAK)–signal transducer and activator of transcription 3 (STAT3) signal cascade in end-stage failing human hearts with the cardiac phenotype of mice harboring systemic or cardiac-restricted knockouts in this cascade. The left side indicates the alterations in the IL-6–gp130–JAK–STAT3 cascade in end-stage human dilated cardiomyopathy in comparison with normal myocardium: Serum levels of IL-6 are upregulated and myocardial IL-6 protein levels are reduced; gp130 protein levels are not altered, but their activation stage (tyrosine phosphorylation) is enhanced; JAK2 activation (tyrosine phosphorylation) is diminished with no alteration in protein expression; STAT3 is reduced at both the protein level and the activation stage (tyrosine phosphorylation) (60–62). The right side summarizes the cardiac phenotypes of mice with mutations in the IL-6–gp130–JAK–STAT3 signaling cascade. Mice with systemic deletion of IL-6 (IL-6–/–) have no apparent cardiac phenotype at baseline or after myocardial infarction (69); mice with cardiac-restricted deletion of gp130 (-myosin heavy chain [MHC]-Cretg/–; gp130flox/flox) appear normal at baseline but show early cardiac failure and enhanced mortality after pressure overload induced by thoracic aortic constriction (TAC) (63). Mice with cardiac-restricted deletion of STAT3 (-MHC-Cretg/–; STAT3flox/flox) develop an age-related dilated cardiomyopathy (67,68) and are more susceptible to ischemic injury (67). In summary, the gp130–STAT3 cascade seems to promote hypertrophy, cardioprotection, and angiogenesis in the stressed heart (4,63–66,68).

View larger version (33K): [in this window] [in a new window] [Download PPT slide]   Figure 3 Sensing and transmission of stress signaling in cardiomyocyte exposed to biomechanical stretch. Mechanical strain induces activation of integrins (,ß) by different ligands in the extracellular matrix (e.g., collagen, fibronectin, laminin), initiating signaling of multiple intracellular pathways. Melusin (Mel), an integrin-bound protein, transduces the stress signal from the cell membrane to the nucleus by activating protein kinase B (Akt)-glycogen synthase kinase (GSK)-3ß, thereby promoting the dephosphorylation (activation and nuclear location) of the prohypertrophic transcription factor nuclear factor of activated T-cells (NF-AT3). NF-AT3 then contributes to the induction of a prohypertrophic gene program and subsequent cardiomyocyte hypertrophy (80,87,93). A second stress-sensing pathway involves muscle LIM protein (MLP), a Z-disc protein, which with others, such as -actinin (-act), telethonin (T-cap), vinculin (Vin), and talin (Tal), is anchored to integrins (,ß) at the plasma membrane and to the sarcomere. This molecule complex connects the contractile machinery to the extracellular matrix proteins laminin and collagen (87). MLP acts as an anchoring protein for other Z-disc proteins, e.g., for T-cap, and seems to be necessary to keep these proteins in place during contraction (81). In addition, MLP functions as an anchoring protein for calcineurin at the Z-disc, where it brings calcineurin in close approximation with T-tubular L-type Ca2+-channels, which are implicated in calcineurin activation by Ca2+/calmodulin after Ca2+ influx. Activation of calcineurin then promotes the activation of NF-AT3, resulting in hypertrophic gene expression (91,115).

View larger version (74K): [in this window] [in a new window] [Download PPT slide]   Figure 4 Angiogenic circuits in the heart. (A) Immunohistochemical staining for isolectin B4 in in-situ fixed myocardial cross-section shows reduced capillary density in 4-month-old -MHC-Cretg/–; STAT3flox/flox male mice compared with age-matched wild-type (WT) sibling males (67). (B) Chronic pressure overload augments capillary density in JunD knockout male mice (JunD–/–) to a higher degree than in WT sibling male mice, as shown by triple staining for isolectin B4 (yellow), cell membrane marker wheat germ agglutinin (red), and nuclear stain Hoechst (blue) (101). (C) Immunohistochemical staining shows high expression of CCN1 protein in cardiomyocytes and blood vessels of a left ventricular (LV) section from a patient with end-stage heart failure caused by ischemic cardiomyopathy (ICM) compared with low CCN1 staining in a LV section from a nonfailing human heart. The MHC staining of a serial ICM section with an antibody-detecting sarcomeric myosin heavy chain identifies cardiomyocytes as a source of CCN1 (106). Other abbreviations as in Figure 3.