Table 1 Candidate genes and their functions in hypertensive LHV pathogenesis

RENAL-ANGIOTENSIN SYSTEM/G-COUPLED PROTEIN RECEPTORS:

ATP6AP2

Xp11.4

Muscular smooth muscle contraction. Renin and prorenin cellular receptor. May mediate renin-dependent cellular responses by activating ERK1 and ERK2. By increasing the catalytic efficiency of renin in AGT/angiotensinogen conversion to angiotensin I, it may also play a role in the renin-angiotensin system (RAS).

Estrogen receptor signaling:

EGFR

7p11.2

Receptor binding to epidermal growth factor. Required by AngII to mediate ERK activation thus plays a critical role in the LVH induced by Ang II.

EGF

4q25

Shedding of heparin-binding EGF by ADAM12, induce hypertrophic signaling via EGFR activation downstream through small G proteins and the MAPK pathway.

ADAM12

10q26.2

Involved in skeletal muscle regeneration, specifically at the onset of cell fusion and macrophage-derived giant cells (MGC) and osteoclast formation from mononuclear precursors. Plays a centre role in cardiac hypertrophy by interacting with HB-EGF.

ERBB2

17q21.1

A member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases. Essential in cardiac development. Involved in the EGFR signaling that drives many cellular responses, including changes in gene expression, cytoskeletal rearrangement, anti-apoptosis and increased cell proliferation.

ITGB2 (Beta-integrin)

21q22.3

Involved in cell adhesion as well as cell-surface mediated signalling. Links the extracellular matrix to the intracelluar cytoskeleton. Stretch sensor. Deletion of this gene/protein leads to cardiac pathology. Gene expression profile is upregulated in ERbeta knockout mice with cardiac hypertrophy.

ITGB1BP2 (Melusin)

Xq13.1

Integrin interacting protein. Sensor of mechanical stress in cardiac myocytes. An essential component for the phosphorylation (inactivation) of GSK3-beta. Deletion of this gene leads to cardiac pathology.

CALCINEURIN-CALMODULIN Ca ²⁺ Signaling:

PPP3CA (calcineurin A-alpha)

4q24

Calcium dependent, calmodulin stimulated protein phosphatase.Ca2+/calmodulin binding.

CALM1 (calmodulin 1)

14q32.11

Mediates the control of large number of enzymes and other proteins by Ca²⁺. Involved in a genetic pathway that regulates the centrosome cycle and progression via cytokinesis.

CALM3 (calmodulin 3)

19q13.2

Together with CALM1 and CALM2, these calmodulin genes give rise to five transcripts that are present in most tissues. This gene may be specifically and differently regulated during cardiac cell proliferation and/or hypertrophy.

CAMK2B (calmodulin kinase)

7p14.3

Calmodulin/Ca²⁺ signaling. At basal Ca²⁺ levels, CaMKs are maintained in a dormant state through autoinhibition. Increase in Ca²⁺ levels allows calmodulin to relieve this autoinhibition and activate the kinase activity.

Ion channel pathway:

Sodium-Calcium exchange pathway

SLC8A1 (NCX1)

2p22.1

SLC9A2 (NHE)

2q12.1

Sodium-Hydrogen exchange pathway

KCNB2

8q13.3

Regulate the smooth muscle contraction by controlling the influx of Ca²⁺ through voltage-gated Ca²⁺ channels

NFAT SIGNALING & OTHERS TRANSCRIPTION FACTORS:

NFATC3

16q22.1

Required in muscle cell, and heart development, as well as smooth muscle differentiation. Rapid nuclear exit of NFATC is thought to be onemechanism by which cells distinguish between sustained and transient calcium signals.

ILF3

19p13.2

Involved in the NFAT transcription signaling. A subunit of the nuclear factor of activated T-cells (NFAT).

ITPR3@ IPR3

6p21.31

Inositol 1,4,5-triphosphate receptor type 3. Involved in mediating the release of intracellular calcium.

GATA4

8p23.1

Transcription factors that regulate genes critical for myocardial differentiation and function, regulates hypertrophic gene expression.

MCIP-1 (RCAN1)

21q22.12

Modulatory calcineurin interacting protein. Serves as calcineurin–regulatory protein that inhibit calcineurin when over expressed.

MEF2A

15q26.3

Transcription factor of cardiac hypertrophy cascade. Involved in the activation of numerous growth factor- and stress-induced genes. Mediates cellular functions in skeletal and cardiac muscle development.

MAPK3

16p11.2

Act as a signaling cascade that regulates various cellular processes including proliferation, differentiation and cell cycle progression in response to a variety of extracellular signals.

JAK2

9p24.1

Involved in a specific subset of cytokine receptor signaling pathways. Uponreceptor activation JAKs phosphorylate the transcription factors known as STATs and initiate the JAK-STATsignaling pathway.

CTNNB1 (Beta-catenin)

3p22.1

Cadherin-associated protein. Part of a complex of proteins that constitute adherens junctions. Involved in the regulation of cell adhesion. Predominantly localized to the cell membrane, and is part of E-cadherin/catenin adhesion complexes which are believed to couple cadherins to the actin cytoskeleton. Structural changes of the extracellular matrix in LVH are significantly modulated by B-catenin associated signaling pathways.