Key Words: heart Ⅲ cardiac fibroblast Ⅲ extracellular matrix Ⅲ Periostin Ⅲ transforming growth factor-␤ signaling A lthough noncardiomyocytes constitute the majority of the cell types present in the postnatal heart and form the cardiac skeleton within which the cardiac myocytes reside, relatively little is known about how the cardiac interstitial microenvironment is formed and the source of the cardiac fibroblast (CF) lineage. The signals that trigger a secretory fibroblast phenotype and collagen formation (fibrogenesis) as well as the morphogenesis of the CF lineage are also not well understood. The CF is the most abundant noncardiomyocyte cell type present within the postnatal mature heart and is chiefly responsible for deposition of the extracellular matrix (ECM). The ECM is considered a dynamic modulatory network because of the continuous changes in secretory activity which alters both cell environment and response throughout development. Indeed, far from inert, the ECM is characterized by constant reorganization in response to endogenous and exogenous stimuli. 1 The ECM also provides structural support for cardiac myocytes and formation of the elaborate cardiac skeleton. The cardiac skeleton encodes the 3D structure of the heart and is composed of a tough sheet of fibrous connective tissue that electrically isolates the atria from the ventricles, contains all four valves and valvular anchorage tissues, and serves as an attachment site for cardiac muscle fibers.Balanced synthesis 2 and degradation 3-5 of this ECM is key to normal cardiovascular development, physiological growth Original

Metabolic syndrome is associated with insulin resistance and atherosclerosis. Here, we show that deficiency of one or two alleles of ATM, the protein mutated in the cancer-prone disease ataxia telangiectasia, worsens features of the metabolic syndrome, increases insulin resistance, and accelerates atherosclerosis in apoE-/- mice. Transplantation with ATM-/- as compared to ATM+/+ bone marrow increased vascular disease. Jun N-terminal kinase (JNK) activity was increased in ATM-deficient cells. Treatment of ATM+/+apoE-/- mice with low-dose chloroquine, an ATM activator, decreased atherosclerosis. In an ATM-dependent manner, chloroquine decreased macrophage JNK activity, decreased macrophage lipoprotein lipase activity (a proatherogenic consequence of JNK activation), decreased blood pressure, and improved glucose tolerance. Chloroquine also improved metabolic abnormalities in ob/ob and db/db mice. These results suggest that ATM-dependent stress pathways mediate susceptibility to the metabolic syndrome and that chloroquine or related agents promoting ATM activity could modulate insulin resistance and decrease vascular disease.

Periostin (gene

Hyperlipidemia promotes the chronic inflammatory disease atherosclerosis through poorly understood mechanisms. Atherogenic lipoproteins activate platelets, but it is unknown whether platelets contribute to early inflammatory atherosclerotic lesions. To address the role of platelet aggregation in diet-induced vascular disease, we studied ␤3 integrin-deficient mice (lacking platelet integrin ␣IIb␤3 and the widely expressed nonplatelet integrin ␣v␤3) in two models of atherosclerosis, apolipoprotein E (apoE)-null and low-density lipoprotein receptor (LDLR)-null mice. Unexpectedly, a high-fat, Western-type (but not a low-fat) diet caused death in two-thirds of the ␤3 ؊/؊ apoE ؊/؊ and half of the ␤3 ؊/؊ LDLR ؊/؊ mice due to noninfectious pneumonitis. In animals from both models surviving high-fat feeding, pneumonitis was absent, but aortic atherosclerosis was 2-to 6-fold greater in ␤3 ؊/؊ compared with ␤ ؉/؉ littermates. Expression of CD36, CD40L, and CD40 was increased in lungs of ␤3 ؊/؊ LDLR ؊/؊ mice. Each was also increased in smooth muscle cells cultured from ␤3-deficient mice and suppressed by retroviral reconstitution of ␤3. These data show that the platelet defect caused by ␣IIb␤3 deficiency does not impair atherosclerotic lesion initiation. They also suggest that ␣v␤3 has a suppressive effect on inflammation, the loss of which induces atherogenic mediators that are amplified by diet-induced hyperlipidemia.

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