Cardiovascular Phenotypes
Specialization of Tissues
Cells have evolved protein types unique to their specialized function
All cell have the same
genotype
but only express a unique set of pps,
phenotype
Specialization of organs (organotype) and cells (phenotype) occurs during development
Commitment
= entry of cell into a particular
lineage
Cardyomyocyte lineage
results from
commitment
of anterio lateral plate mesoderm via adjacent endodermal signal.
Induction
= a signal instructs a cell to enter a lineage or to differentiate.
Determination
= cell’s fate is set and not responsive to external cues.
Differentiation
of committed myocyte progenitors into muscle cells is evident during cardiac tube formation as muscle specific proteins are expressed
1
st
organ to form and function during vertebrate development
cytoskeletal: actins, myosins
electrical
: Na/K and transport channels
excitation-contraction coupling
: Ca
++
channels and transporters
Vascular smooth muscle
cell differentiation is early: actin and myosin expressed in mesenchymal cells adjacent to vascular epithelium
The muscle gene program
Lineages express common as well as distinct gene products and regulatory programs to generate unique phenotypes
Transcription factors regulate the gene program to yield different protein isoforms
Isoforms produced by either
selective transcription
or
alternative splicing
Isoforms express functional and structural differences (mechanical, EC coupling and metabolic systems)
Sublineage = fiber type (i.e. fast vs slow = simplification based on function [force development])
Heart muscle morphological development
Regulatory molecules
Þ
primitive tube
Þ
functionally unique chamber
GATA, MEF2 and Nkx
necessary for the formation of heart muscle
dHAND and eHAND
regulate right and left ventricle development respectively
Vitamin D receptor
(nuclear receptor super family)
Þ
atrial specification
Little known about SM transcription regulation and tissue specific mRNA alternative splicing in cardiac+SM
Isoforms switch throughout development for all muscle tissues
Can occur during development: due to innervation, hormonal changes (retinoids), ppGF (TGF’s and FGF’s) and mechanical activity
Þ
affect transcrip. process Many transitions occur at birth: due to mechanical loading and neurohormonal changes (
Ý
TH levels)
Most mature tissues can
recapitulate the fetal gene program
and switch from fast to slow twitch in response to increased pressure
Ventricular Expression: ANF and
MLC
A
ß
before birth, MHC
b
Þ
MHC
a
Ý
MCAD and SERCA2 before birth
Þ
PP
Atrial Expression: before birth MLC-1
V
ß
and MLC-2
V
never expressed
differences in EC coupling and metabolism at birth
(1)
Ý
SR proteins (SRCaATPase)
(2)
Ý
FA metabolic proteins (MCAD, VCAD)
Cardiac Ventricular developmental transition
Myosin ATPase activity
Ý
Ca sensitivity of Thin filament complex
ß
Quantity Ca Cycled per beat
Ý
heart changes from glycolytic
Þ
FA metabolism
These changes represent a slow-to-fast transition so mature ventricles can produce more power than the embryonic ventricles