Trends in Biochemical Sciences
The biochemical response of the heart to hypertension and exercise
Section snippets
Physiological and pathological remodeling of the heart
In contrast to physiological remodeling, remodeling caused by hypertension is a major risk factor for – and the resulting left ventricular hypertrophy is a strong predictor of – heart failure [3]. The fibrosis caused by hypertension reduces the level of three-dimensional organization in the heart muscle and increases the stiffness of the myocardium, which reduces filling of the heart during diastole [4]. Apoptosis of cardiomyocytes can reduce contractile force, diminish myocardial wall
Ligand-dependent signaling pathways that lead to cardiac hypertrophy
Cardiac hypertrophy can be also initiated and regulated by neurohumoral stimulation and by autocrine and paracrine factors via signaling mechanisms involved in the response to pressure overload 29, 30. The sympathetic nervous system can activate hypertrophic remodeling through the stimulation of α1 adrenergic receptors [31]. Nevertheless, transgenic mice that express constitutively active α1B receptors develop dilated cardiomopathy and die from heart failure [29].
Perhaps the most intensely
Changes in cellular structure and organization in cardiac hypertrophy
The mechanical and biochemical signals described above control mechanical and electrical connections among cardiomyocytes and also regulate the development of their cytoskeletal structure. Inhibition of GSK3β stabilizes β-catenin, enabling it to translocate into the nucleus to induce the transcription of connexin43 – the principal constituent of cardiac gap junctions [39]. Accumulation of β-catenin at intercalated discs in hypertrophic myocytes [40], together with an upregulation of connexin43,
Mechanotransduction machinery
Myocardial remodeling in response to pressure overload results from interplay between mechanical and biochemical signals [29]. Signals initiated by stretching cardiomyocytes are transduced via integrins that are linked across the cell membrane to the cytoskeleton. Both in a perfused heart (isolated from circulating agonists) [51] and in an intact animal [52], stretching or pressure overload causes rapid tyrosine phosphorylation of the focal adhesion kinase (FAK), followed by its binding to the
The roles of fibroblasts in cardiac hypertrophy
What is the relationship between physiological and pathological hypertrophy? Physiological and, initially, pathological hypertrophy strengthen the heart as it responds to the increase in demand. Over time, additional maladaptive processes begin in the pathological response, including apoptosis of cardiomyocytes and the development of fibrosis. If we assume that both types of hypertrophy in myocytes are similar, then additional processes must produce the pathological response. One of the most
Concluding remarks
Important dualities characterize cardiac hypertrophy: physiological versus pathological, induction by pressure overload versus induction by agonists, and contributions of cardiomyocytes versus contributions of fibroblasts. Indeed, none of these pairs is mutually exclusive – each branch overlaps its opposing branch to some degree. In addition, all of them raise outstanding issues (Box 3).
Recent research has revealed much information that characterizes each of these oppositions. Nevertheless, the
Acknowledgements
We are grateful to the referees for constructive and informative comments.
Glossary
- Ventricular hypertrophy:
- An increase in ventricular mass that occurs as an adaptation to greater mechanical stress caused by a rise in pressure or volume.
- Cardiomyocytes:
- Heart muscle cells.
- Frank–Starling mechanism:
- The ability of the heart to boost its stroke volume (strength of contraction) in response to an increase in blood volume.
- Fibrosis:
- A disproportionate increase in the nonmyocyte compartment of the myocardium that includes fibroblasts and collagen.
- Sarcomeres:
- Repeating structures of actin
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