Hypertrophy vs apoptosis: what are the relevant triggers?

Cardiac remodeling may be defined as genome expression resulting in molecular, cellular, and interstitial changes and manifested clinically as changes in the size, shape, and function of the heart. In response to various pathologic stimuli (myocardial infarction, pressure/volume overload, idiopathic dilated cardiomyopathy, and myocarditis), cardiac myocytes stretch and local hormone and cytokine release increases. These changes, in turn, stimulate the expression of embryonic genes. Thus, myocytes, which are typical terminally differentiated cells, become capable of a life-death cycle. In other words, the failing myocyte may survive by hypertrophy or kill itself by apoptosis in response to the same initial pathologic stimulus. It is thought that rapid progression to fullblown heart failure results from myocyte apoptosis predominating over myocyte hypertrophy; this decreases the force of contraction and encourages ventricular dilatation.

Apoptosis, or programmed cell death, is an active process regulated by the nucleus. It is characterized by the fragmentation of nuclear DNA by specific endonucleases, giving a ladder pattern on gel electrophoresis contrasting with the DNA smear typical of necrosis, defined as nonprogrammed immunomedi-ated cell death.

Myocardial hypertrophy is an early milestone in the clinical course of heart failure, and an important risk factor for subsequent cardiac morbidity and mortality. In response to the pathologic stimuli listed above, the heart adapts to increased demands for cardiac work by increasing its muscle mass through the initiation of a hypertrophic response. The assembly of contractile protein units in series characterizes the eccentric hypertrophy that occurs in dilated cardiomyopathy, with a greater increase in myocyte length than width. In pressure overload, new contractile protein units are assembled in parallel, resulting in a relative increase in the width of individual cardiac myocytes and therefore in concentric hypertrophy.

Both myocytes and nonmyocytes are direct biomechanical sensors of hemodynamic load. The release of growth factors and cytokines generates growth signals, prompting a local response. The factors involved include endothelin-1, angiotensin II, insulin-like growth factor-1, and other growth factors that activate either heteromeric Gqa protein or low-molecular-weight guanosine triphosphate (GTP)-binding Ras protein signaling pathways, as well as cardiotrophin-1 and other members of the interleukin-6 cytokine family that activate cellular response by means of the transmembrane signal transducer gp 130, which activates a typical antiapoptotic pathway.

According to in vitro and in vivo results, the primary downstream effectors of the above signaling pathways are the mitogen-activated protein kinases, including c-jun N-terminal kinase and p38. These kinases are particularly important switches in the pathways between apoptosis and adaptive hypertrophy. For example, in mice, p38 mitogen activated protein kinases are strongly activated by pressure overload, while upstream kinases that specifically activate p38 cause the growth of cultured myocytes. However, the activation of p38 is also accompanied by an increase in the rate of apoptosis. The a and P isoforms of p38 have opposite effects: p38a increases apoptosis, p38(3 inhibits it.

Well-known triggers of apoptosis other than cardiac hypertrophy in pressure overload include cytokines (especially tumor necrosis factor-a [TNF-a] and the interleukins), oxidative stress, and mitochondrial damage. TNF-a exerts its cellular action via two specific receptors,2 TNFR1 and TNFR2. TNFR1 interacts with distinct cytosolic proteins sharing the death domain, a fitting designation in that this interaction activates various pathways that ultimately cause cell death through oxidative stress and mitochondrial damage.

In conclusion, heart failure may be viewed as a progressive multistep process involving physiologic and molecular initiators, promoters, suppressors, and effectors of the chronic course to heart muscle failure. Further unraveling of the signals causing the specific features of heart failure, coupled with the growing human genome database, should ultimately enable us to identify targets whose actions we can interrupt, thereby halting or perhaps reversing clinical deterioration.


pathophysiology; cardiac remodeling; myocardial hypertrophy; apoptosis; cytokine; TNF-a; kinase

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