Despite declines in heart failure morbidity and mortality with current therapies, rehospitalization rates remain distressingly high, substantially affecting individuals, society, and the economy. As a result, the need for new therapeutic advances and novel medical devices is urgent. Disease-related left ventricular remodeling is a complex process involving cardiac myocyte growth and death, vascular rarefaction, fibrosis, inflammation, and electrophysiological remodeling. Because these events are highly interrelated, targeting a single molecule or process may not be sufficient. Here, we review molecular and cellular mechanisms governing pathological ventricular remodeling.

Pathological Ventricular Remodeling Mechanisms: Part 1 of 2

The mitogen-activated protein (MAP) kinase cascades play essential roles in a variety of cell processes by influencing transcriptional or translational regulation. ERKs play a central role in survival and mitogenic signaling, while JNKs and p38 MAP kinases are preferentially activated by environmental stresses and are actively involved in various stress responses including cell death, survival and differentiation. Apoptosis signal-regulating kinase 1 (ASK1)--a serine/threonine protein kinase--is a member of the MAPKKK family and activates both JNK and p38 pathways. It is well known that ASK1 is activated in cells treated with death receptor ligands and oxidant stress, such as that caused by hydrogen peroxide (H2O2). Moreover, recent studies have revealed new mechanisms by which ASK1 is activated in response to various types of extracellular and intracellular signals, such as endoplasmic reticulum (ER) stress, calcium signaling, and G-protein coupled receptor (GPCR) signaling. This review summarizes the regulatory mechanisms of ASK1 activity and the physiological roles of ASK1-mediated signal transduction.

The ASK1-MAP Kinase Cascades in Mammalian Stress Response

Granulation tissue formation is a critical step in infarct repair, however, the kinetics of cell replication and the molecules that regulate this process are poorly understood. In uninjured mouse hearts and at 2 days post-infarction, very little DNA synthesis (measured by incorporation of a BrdU pulse) was detected in any cell type. Four days after permanent coronary occlusion, the rates of myofibroblast (smooth muscle α-actin and BrdU double-positive) and endothelial cell (CD31 and BrdU double-positive) proliferation were 15.4 ± 1.1% and 2.9 ± 0.5%, respectively. Most proliferating cells were located at the interface of the infarct and viable tissue. By 1 week, fibroblast and endothelial cell proliferation declined to 4.1 ± 0.6% and 0.7 ± 0.1%, respectively. In the 2-week infarct, the remaining necrosis had been phagocytosed, and fibroblast and endothelial cell proliferation were 2 ) declined from 3643 ± 82 in control hearts to 2716 ± 197 at 1 week and 1010 ± 47 at 4 weeks post-myocardial infarction (MI). The average percent area occupied by vessels did not change significantly between the groups but the area/vessel (μm 2 ) increased from 14.1 ± 0.3 in control hearts to 16.9 ± 1.9 at 1 week and 38.7 ± 7.9 at 4 weeks post-MI. These data indicate that mitogens for fibroblasts and endothelial cells peak within 4 days of infarction in the mouse heart. This provides the basis for identifying the responsible molecules and developing strategies to alter wound repair and improve cardiac function.

Myofibroblast and endothelial cell proliferation during murine myocardial infarct repair

Mitochondrial quality control mechanisms as molecular targets in cardiac ischemia-reperfusion injury.

Apoptosis and oxidants in the heart.

We assessed ANG II type 1 (AT1) and type 2 (AT2) receptor (R) expression and functional recovery after ischemia-reperfusion with or without AT1R/AT2R blockade in isolated working rat hearts. Groups...

https://www.physiology.org/doi/pdf/10.1152/ajpheart.00839.2000

AT1 and AT2 receptor expression and blockade after acute ischemia-reperfusion in isolated working rat hearts

ObjectiveTo determine whether chronic angiotensin (AngII) type I receptor (AT1R) blockade inhibits cardiomyocyte (CM) apoptosis and attenuates left ventricular (LV) dysfunction after ischemia–reperfusion (IR) in the isolated working rat heart.MethodsPostischemic recovery of LV developed pressure, th

Postischemic apoptosis and functional recovery after angiotensin II type 1 receptor blockade in isolated working rat hearts.

Mitogen-activated protein kinases (MAPKs) have been implicated during ischemia-reperfusion (IR) and angiotensin II (AngII) type 2 receptor (AT2R) blockade has been shown to induce cardioprotection involving protein kinase Cepsilon (PKCepsilon) signaling after IR. We examined whether the 3 major MAPKs, p38, c-Jun NH2-terminal kinase (JNK-1 and JNK-2), and extracellular signal regulated kinases (ERK-1 and ERK-2) are activated after IR and whether treatment with the AT2R antagonist PD123,319 (PD) alters their expression. Isolated rat hearts were randomized to control (aerobic perfusion, 80 min), IR (no drug; 50 min of perfusion, 30 min global ischemia and 30 min reperfusion; working mode), and IR + PD (0.3 micromol/l) and left ventricular (LV) work was measured. We measured LV tissue content of p38, p-p38, p-JNK-1 (54 kDa), p-JNK-2 (46 kDa), p-ERK-1 (44 kDa), p-ERK-2 (42 kDa) and PKCepsilon proteins by immunoblotting and cGMP by enzyme immunoassay. IR resulted in significant LV dysfunction, increase in p-p38 and p-JNK-1/-2, no change in p-ERK-1/-2 or PKCepsilon, and decrease in cGMP. PD improved LV recovery after IR, induced a slight increase in p-p38 (p < 0.01 vs. control), normalized p-JNK-1, did not change p-ERK-1/-2, and increased PKCepsilon and cGMP. The overall results suggest that p38 and JNK might play a significant role in acute IR injury and the cardioprotective effect of AT2R blockade independent of ERK. The activation of p38 and JNKs during IR may be linked, in part, to AT2R stimulation.

Effect of angiotensin II type 2 receptor blockade on mitogen activated protein kinases during myocardial ischemia-reperfusion

Angiotensin II and cardiomyocyte apoptosis in the SHR

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