Inherited Cardiomyopathies Can Arise From Disorders of Cardiac Energy Metabolism or Abnormal Myocardial Proteins

 Acardiomyopathyis any structural or functional abnormality of the ventricular myocardium. These abnormalities can arise from a number of causes, many of them hereditary. As shown in Table 1, the causes of inherited cardiomyopathies fall into two broad classes: (1) disorders of cardiac energy metabolism, mainly reflecting mutations in genes encoding enzymes or proteins involved in fatty acid oxidation (a major source of energy for the myocardium) and oxidative phosphorylation; (2) mutations in genes encoding proteins involved in or affecting myocardial contraction, such as myosin, tropomyosin, the troponins, and cardiac myosin-binding protein C.

Table1. Biochemical Causes of Inherited Cardiomyopathies ^a

Mutations in the Cardiac β-Myosin Heavy-Chain Gene Are One Cause of Familial Hypertrophic Cardiomyopathy

Familial hypertrophic cardiomyopathy is one of the most commonly encountered hereditary cardiac diseases. Patients exhibit hypertrophy—often massive—of one or both ventricles, starting early in life. Most cases are transmitted in an autosomal dominant manner; the rest are sporadic. The root cause of this condition is any one of several missense mutations in the gene encoding the β-myosin heavy chain that leads to the replacement of a highly conserved amino acid with some other residue. The substitutions cluster in the head and head-rod regions of the myosin heavy chain. One hypothesis is that these heavy chain variants (“poison polypeptides”) cause formation of abnormal myofibrils, eventually resulting in compensatory hypertrophy.

Patients with familial hypertrophic cardiomyopathy can show great variation in clinical picture. This in part reflects genetic heterogeneity as it appears that mutations in a number of other genes (eg, those encoding cardiac actin, tropomyosin, cardiac troponins I and T, essential and regulatory myosin light chains, cardiac myosin-binding protein C, titin, and mitochondrial tRNA-glycine and tRNA-isoleucine) may also cause familial hypertrophic cardiomyopathy. Patients harboring mutations that are predicted to alter the charge character of the affected amino acid side chain exhibit a significantly shorter life expectancy than patients in whom the mutation produced no alteration in charge.

Mutations in the genes encoding dystrophin, muscle LIM protein (so called because it was found to contain a cysteine rich domain originally detected in three proteins: Lin-II, Isl-1, and Mec-3), the cyclic AMP response-element binding protein (CREB), desmin, and lamin have each been implicated in the causation of dilated cardiomyopathy. The first two proteins help organize the contractile apparatus of cardiac muscle cells, while CREB regulates the expression of several genes within these cells.

Mutations in the Gene Encoding Dystrophin Cause Duchenne Muscular Dystrophy

Other protein components of the contractile apparatus include titin, the world’s largest known protein whose role is to anchor the ends of myofibrils, nebulin, α-actinin, desmin, and dystrophin. Among these proteins, dystrophin is of particular biomedical interest. Mutations in the gene that encodes it play a causative role in Duchenne muscular dystrophy and Becker muscular dystrophy and have been implicated in dilated cardiomyopathy. Dystrophin bridges the actin cytoskeleton to the extracellular matrix at the interior face of the plasma membrane. Formation of this link is necessary for assembly of the synaptic junction. Duchenne muscular dystrophy appears to result from the inability of mutationally altered forms of dystrophin to support formation of functionally competent synaptic junctions. Similarly, mutations in genes encoding the glycosyltransferases that modify α-dystroglycan or those encoding polypeptide components of the sarcoglycan complex (Figure 1) are responsible for certain other congenital forms of muscular dystrophy such as limb-girdle.

Fig1. Organization of dystrophin and other proteins in relation to the plasma membrane of muscle cells. Dystrophin is part of a large oligomeric complex associated with several other protein complexes. The dystroglycan complex consists of α-dystroglycan, which associates with the basal lamina protein merosin (also named laminin-2, see Chapter 50), and α-dystroglycan, which binds α-dystroglycan and dystrophin. Syntrophin binds to the carboxyl terminal of dystrophin. The sarcoglycan complex consists of four transmembrane proteins: α-, β-, γ-, and δ-sarcoglycan. The function of the sarcoglycan complex and the nature of the interactions within the complex and between it and the other complexes are not clear. The sarcoglycan complex is formed only in striated muscle, and its subunits preferentially associate with each other, suggesting that the complex may function as a single unit. Mutations in the gene encoding dystrophin cause Duchenne and Becker muscular dystrophies. Mutations in the genes encoding the various sarcoglycans have been shown to be responsible for limb-girdle dystrophies (eg, OMIM 604286) and mutations in genes encoding other muscle proteins cause other types of muscular dystrophy. Mutations in genes encoding certain glycosyltransferases involved in the synthesis of the glycan chains of α-dystroglycan are responsible for certain congenital muscular dystrophies. (Reproduced with permission from Duggan DJ, Gorospe JR, Fanin M, et al: Mutations in the sarcoglycan genes in patients with myopathy, N Engl J Med. 1997;336(9):618–624.)

Nitric Oxide Relaxes the Smooth Muscle of Blood Vessels

Acetylcholine triggers the relaxation of the smooth muscle of blood vessels. On binding to its cell surface receptors on the endothelial cells surrounding vascular smooth muscle cells, acetylcholine triggers the activation of associated phospholipases on the interior surface of the plasma membrane. Phos pholipases hydrolyze and release the polyphosphorylated head groups, particularly 3,4,5-triphosphoinositol, from phosphatidylinositol, a quantitatively minor but functionally important phospholipid component of the plasma membrane. These polyphosphoinositol second messengers initiate the release of Ca2+ into the cytoplasm of these vascular epithelial cells, which in turn triggers the release of endothelium-derived relaxing factor (EDRF), which diffuses into the adjacent smooth muscle where it causes subsequent relaxation. EDRF was identified as NO,nitrous oxide, which has a half-life of only ~3-4 s in tissues.

NO synthase, a Ca2+-activated enzyme found in the cytosol, catalyzes the five-electron oxidation of a guanidino nitro gen in the side chain of arginine, yielding citrulline and NO (Figure 2). This complex reaction utilizes NADPH and four redox-active prosthetic groups: FAD, FMN, heme, and tetrahydrobiopterin. On diffusing into the surrounding vascular smooth muscle cells, NO binds to the heme moiety of a soluble guanylyl cyclase, activating the enzyme and elevating the intracellular levels of the second messenger 3′,5′-cyclic GMP (cGMP). This in turn stimulates the activities of certain cGMP-dependent protein kinases, which phosphorylate specific muscle proteins, causing relaxation.

Fig2. Diagram showing formation in an endothelial cell of nitric oxide (NO) from arginine in a reaction catalyzed by NO synthase. Interaction of an agonist (eg, acetylcholine) with a receptor (R) leads to intracellular release of Ca2+ induced by inositol trisphosphate generated by the phosphoinositide pathway, resulting in activation of NO synthase. The NO subsequently diffuses into adjacent smooth muscle, where it leads to activation of guanylyl cyclase, formation of cGMP, stimulation of cGMP protein kinases, and subsequent relaxation. The vasodilator nitroglycerin is shown entering the smooth muscle cell, where its metabolism also leads to formation of NO.

NO can also be formed from nitrite, derived from the metabolism of vasodilators such as glyceryl trinitrate, also known as nitroglycerin, which is commonly administered to treat angina. Another important cardiovascular effect of NO is the inhibition of platelet aggregation, a consequence of the increased synthesis of cGMP.

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مواضيع ذات صلة

Skeletal Muscle Contains Slow (Red) & Fast (White) Twitch Fibers

Muscle Contraction Requires Large Quantities of ATP

Cardiac Muscle Resembles Skeletal Muscle in Many Respects

Contraction is Orchestrated by the Second Messenger Ca2+

Muscle Converts Chemical Energy to Mechanical Energy

Cholesterol Side Chain Cleavage Enzyme (p450scc)

Steroidogenic Acute Regulatory Protein (StAR)

Cytochrome P450 Steroid Hydroxylases

Major Protein Components of Muscle Fibers

The Major Components of Cartilage are Type II Collagen & Certain Proteoglycans

Bone is Affected by many Metabolic & Genetic Disorders

The Assembly of Membranes is Complex